TWI761826B - Salts of diaminopyrimidine compounds, solid forms thereof, and preparation methods and uses thereof - Google Patents

Abstract

The present invention relates to salts of 5-((2-ethynyl-5-isopropylpyridin-4-yl)oxy)pyrimidine-2,4-diamine and solid forms thereof, methods for preparing the solid forms, comprising the Pharmaceutical compositions in solid form, and use of the solid form for the prevention or treatment of diseases modulated by P2X3 and/or P2X2/3 receptor antagonists.

Description

Salts of diaminopyrimidine compounds, solid forms thereof, and preparation methods and uses thereof

The present invention relates to salts of 5-((2-ethynyl-5-isopropylpyridin-4-yl)oxy)pyrimidine-2,4-diamine (hereinafter referred to as "Compound A") and solid forms thereof , a method for preparing the solid form, a pharmaceutical composition comprising the solid form, and the use of the solid form for the prevention or treatment of diseases modulated by P2X3 and/or P2X2/3 receptor antagonists.

Purine compounds act through cell surface purinergic receptors, which exert a wide range of physiological and pathological roles. ATP (and to a lesser extent adenosine) can stimulate sensory nerve endings to produce intense pain and significantly increased sensory nerve firing. According to molecular structure, transduction mechanism and pharmacological characteristics, ATP receptors are divided into two main families, P2Y- and P2X-purinergic receptors. P2Y-purinergic receptors are G-protein coupled receptors, while P2X-purinergic receptors are a family of ATP-gated cation channels. Purinergic receptors, in particular P2X receptors, are known to be capable of forming homomultimers or heteromultimers. To date, cDNAs for multiple P2X receptor subtypes have been cloned, including: six homologous receptors: P2X1, P2X2, P2X3, P2X4, P2X5, and P2X7; three heterologous receptors: P2X2/3, P2X4 /6, P2X1/5. Structural and genetic maps of the P2X3 receptor subunits in the mouse genome have also been reported.

Studies have shown that P2X3 and/or P2X2/3 receptor antagonists can be used to treat diseases such as pain. The applicant has discovered a class of diaminopyrimidine compounds, in particular 5-((2-ethynyl-5-isopropylpyridin-4-yl)oxy)pyrimidine-2,4-diamine, which are useful as potent P2X3 and/or P2X2/3 receptor antagonists (see PCT/CN2018/112829, which is incorporated herein by reference in its entirety).

化合物 A 在另一方面中，本發明提供化合物A的鹽的晶型。In one aspect, the present invention provides a salt of Compound A (5-((2-ethynyl-5-isopropylpyridin-4-yl)oxy)pyrimidine-2,4-diamine) shown below

Compound A In another aspect, the present invention provides a crystalline form of a salt of Compound A.

The preferred crystal forms of the present invention not only have excellent effects in the prevention or treatment of diseases mediated by P2X3 and/or P2X2/3 receptor antagonists, but also have other advantages. For example, the preferred crystalline forms of the present invention have excellent physical properties (including solubility, dissolution rate, light resistance, low hygroscopicity, high temperature resistance, high humidity resistance, fluidity, etc.), and in factors such as bioavailability In terms of properties such as physical and/or chemical stability and ease of preparation, the preferred crystal form of the present invention may have more excellent properties. The preferred crystal form of the present invention has good powder properties, is more suitable and convenient for mass production and can be used to form preparations, can reduce irritation and improve absorption, solve the problem of metabolic rate, and significantly reduce drug accumulation. Toxicity, improve safety, and effectively ensure the quality and efficacy of drug products.

In another aspect, the present invention provides methods of preparing the crystalline forms of the present invention.

In another aspect, the present invention provides pharmaceutical compositions comprising any one or more crystalline forms of the present invention, and one or more pharmaceutically acceptable carriers.

In another aspect, the present invention provides the use of a crystalline form of the present invention in the manufacture of a medicament for the treatment of a disease modulated by a P2X3 and/or P2X2/3 receptor antagonist.

definition

Unless otherwise defined hereinafter, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. References to techniques used herein are intended to refer to techniques commonly understood in the technical field to which the present invention pertains, including those variations or substitutions of equivalent techniques of techniques obvious to those of ordinary skill in the technical field to which this invention pertains. While the following terms are believed to be well understood by those of ordinary skill in the art to which this invention pertains, the following definitions are set forth to better explain the invention.

The terms "comprising," "including," "having," "containing," or "involving," as used herein, and other variations thereof herein, are inclusive or open-ended, and do not Other unlisted elements or method steps are excluded.

The word "about" as used herein refers to what one of ordinary skill in the art to which the invention pertains would consider to be within an acceptable standard error of the value, eg, ±0.05, ±0.1, ±0.2, ±0.3, ±1, ±2 or ±3 etc.

The term "solid form" as used herein includes all solid state forms of the salt of Compound A, such as crystalline or amorphous forms.

The term "amorphous" as used herein refers to any solid substance that is not ordered in three dimensions. In some cases, amorphous solids can be characterized by known techniques including XRPD crystallography, solid state nuclear magnetic resonance (ssNMR) spectroscopy, DSC, or some combination of these techniques. As explained below, amorphous solids produce diffuse XRPD patterns that typically include one or two broad peaks (ie, peaks with a base width of about 5° 2Θ or greater).

The term "crystalline form" or "crystal" as used herein refers to any solid material that exhibits a three-dimensional ordering, as opposed to amorphous solid material, which produces characteristic XRPD patterns with well-defined peaks.

The term "X-ray powder diffraction pattern (XRPD pattern)" as used herein refers to an experimentally observed diffraction pattern or a parameter derived therefrom. XRPD patterns are typically characterized by peak position (abscissa) and/or peak intensity (ordinate).

The term "2Θ" as used herein refers to a peak position in degrees based on an experimental setup of an X-ray diffraction experiment, and is usually the abscissa unit in a diffraction pattern. If the reflection is diffracted when the incident beam forms an angle theta with a lattice plane, the experimental setup requires recording the reflected beam at an angle of 2theta. It should be understood that references herein to particular 2[theta] values for particular crystal forms are intended to represent 2[theta] values (in degrees) measured using the X-ray diffraction experimental conditions described herein. For example, as described herein, Cu-Kα (Kα1 (Å): 1.540598 and Kα2 (Å): 1.544426) were used as radiation sources.

As used herein, "1%" refers to percent peak intensity.

The term "differential scanning calorimetry (DSC) pattern" as used herein refers to a curve recorded by a differential scanning calorimeter. Unless otherwise stated, the temperature mentioned when describing characteristic peaks in the DSC spectrum refers to the onset temperature of the peak.

The term "thermogravimetric analysis (TGA) pattern" as used herein refers to a curve recorded by a thermogravimetric analyzer.

As used herein, the term "substantially the same" with respect to X-ray diffraction peak positions means that representative peak positions and intensity variations are taken into account. For example, one of ordinary skill in the art to which this invention pertains will understand that the peak position (2Θ) will show some variation, typically as much as 0.1-0.2 degrees, and the instrument used to measure diffraction will also show some variation. In addition, those of ordinary skill in the art to which the present invention pertains will understand that relative peak intensities will show inter-instrument variation as well as due to the degree of crystallinity, preferred orientation, the surface of the prepared sample, and as known to those of ordinary skill in the art to which the present invention pertains. changes in other factors. Similarly, as used herein, "substantially the same" with respect to DSC profiles is also intended to encompass variations related to these analytical techniques known to those of ordinary skill in the art to which this invention pertains. For example, there will typically be up to ±0.2°C variation in differential scanning calorimetry for well-defined peaks, and even larger (eg, up to ±1°C) for broad peaks.

The liquid NMR spectra in this application are preferably acquired on a Bruker Advance 300 NMR instrument, unless otherwise stated, using DMSO- d ₆ as the solvent.

Polarizing microscopic data in this application is preferably acquired by a Polarizing Microscope ECLIPSE LV100POL (Nikon, JPN).

Numerical ranges as used herein (eg "1-10", "1-6", "2-10", "2-6", "3-10", "5-10" ", "3-6"), etc., encompass any of the stated ranges of values (eg, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 ).

The prepared salt or its crystalline form can be recovered by methods including decantation, centrifugation, evaporation, gravity filtration, suction filtration, or any other technique for solids recovery under pressure or reduced pressure. The recovered solids can be optionally dried. "Drying" in the present invention is carried out under reduced pressure (preferably vacuum) until the residual solvent content is reduced to the limits given by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use ("ICH") guidelines In the range. The residual solvent content depends on the type of solvent, but does not exceed about 5000 ppm, or preferably about 4000 ppm, or more preferably about 3000 ppm. The drying can be in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluid bed dryer, spin flash dryer, flash dryer, and the like conduct. The drying can be at a temperature below about 100°C, below about 80°C, below about 60°C, below about 50°C, below about 30°C, or any other suitable temperature, under atmospheric pressure or reduced pressure ( preferably under vacuum) for any desired time (eg, about 1, 2, 3, 5, 10, 15, 20, 24 hours, or overnight) that achieves the desired result, as long as the quality of the salt does not deteriorate. The drying can be performed any desired number of times until the desired product quality is achieved. The dried product may optionally undergo a comminution operation to produce the desired fineness. Grinding or micronizing can be performed before drying of the product or after drying is complete. Techniques that can be used to reduce fineness include, but are not limited to, ball, roll, and hammer milling, and jet milling. Salt of compound A , its crystal form and its preparation method

化合物 A 其為無機酸鹽或有機酸鹽，其中 該無機酸選自鹽酸、氫溴酸、氫碘酸、硫酸、硝酸、硼酸、磷酸及其任意組合； 該有機酸選自甲酸、乙酸、乙醯乙酸、三氟乙酸、丙酸、丙酮酸、丁酸、己酸、庚酸、十一烷酸、月桂酸、硬脂酸、棕櫚酸、草酸、丙二酸、琥珀酸、戊二酸、己二酸、馬來酸、富馬酸、乳酸、L-蘋果酸、檸檬酸、L-酒石酸、苯甲酸、水楊酸、肉桂酸、萘甲酸、雙羥萘酸(撲酸)、菸鹼酸、乳清酸、甲基硫酸、十二烷基硫酸、甲磺酸、三氟甲磺酸、乙二磺酸、羥乙基磺酸、對甲苯磺酸、苯磺酸、1,5-萘二磺酸、2-萘磺酸、樟腦磺酸、胺基磺酸、麩胺酸、天門冬胺酸、葡萄糖酸、葡萄糖醛酸及其任意組合。In some embodiments, the present invention provides salts of Compound A,

Compound A is an inorganic acid salt or an organic acid salt, wherein the inorganic acid is selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid and any combination thereof; the organic acid is selected from formic acid, acetic acid, ethyl acetate Acetic acid, trifluoroacetic acid, propionic acid, pyruvic acid, butyric acid, caproic acid, heptanoic acid, undecanoic acid, lauric acid, stearic acid, palmitic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, Adipic acid, maleic acid, fumaric acid, lactic acid, L-malic acid, citric acid, L-tartaric acid, benzoic acid, salicylic acid, cinnamic acid, naphthoic acid, pamoic acid (pamoic acid), nicotine Acid, orotic acid, methyl sulfuric acid, dodecyl sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid, ethanedisulfonic acid, isethionic acid, p-toluenesulfonic acid, benzenesulfonic acid, 1,5- Naphthalenedisulfonic acid, 2-naphthalenesulfonic acid, camphorsulfonic acid, sulfamic acid, glutamic acid, aspartic acid, gluconic acid, glucuronic acid, and any combination thereof.

In a preferred embodiment, the salt of the compound A is selected from L-tartrate, phosphate, mesylate, maleate, hydrochloride, fumarate, citrate, p-toluenesulfonic acid salts and sulfates.

In a preferred embodiment, the present invention provides a salt of Compound A, which is the hydrochloride salt of Compound A; Preferably, the molar ratio of compound A and hydrochloric acid is 1:1; Preferably, the hydrochloride of the compound A is crystal form Ia; The XRPD pattern of this Form Ia includes diffraction angles (2θ) at about 7.8±0.2°, 10.4±0.2°, 15.7±0.2°, 20.0±0.2°, 20.7±0.2°, 22.3±0.2° and 26.0±0.2° characteristic peaks at; Preferably included at about 7.8±0.2°, 10.4±0.2°, 11.1±0.2°, 15.7±0.2°, 16.2±0.2°, 20.0±0.2°, 20.7±0.2°, 22.3±0.2°, 23.7±0.2°, Characteristic peaks at diffraction angles (2θ) of 24.7±0.2°, 26.0±0.2° and 28.8±0.2°; The best include at about 7.8±0.2°, 10.4±0.2°, 11.1±0.2°, 14.5±0.2°, 14.7±0.2°, 15.7±0.2°, 16.2±0.2°, 18.0±0.2°, 20.0±0.2°, 20.7±0.2°, 22.3±0.2°, 23.0±0.2°, 23.7±0.2°, 24.7±0.2°, 25.3±0.2°, 26.0±0.2°, 26.4±0.2°, 27.0±0.2°, 28.8±0.2°, Characteristic peaks at diffraction angles (2Θ) of 29.7 ± 0.2°, 33.9 ± 0.2° and 38.3 ± 0.2°.

In a more preferred embodiment, the XRPD pattern of the Form Ia includes peaks at the following diffraction angles (2θ): Peak number 2θ ( ^o ) ± 0.2 ^o I% Peak number 2θ ( ^o ) ± 0.2 ^o I% Peak number 2θ ( ^o ) ± 0.2 ^o I% 1 7.8° 100 17 23.5° 19.5 33 32.0° 10.9 2 10.4° 68.4 18 23.7° 31.9 34 32.3° 8.7 3 11.1° 41.5 19 24.3° 9.8 35 32.8° 7.8 4 13.1° 11.1 20 24.7° 30.3 36 33.5° 10.3 5 14.5° 18.4 twenty one 25.3° 14.7 37 33.9° 14.3 6 14.7° 16.6 twenty two 26.0° 96.7 38 34.5° 11.6 7 15.7° 82.7 twenty three 26.4° 20.7 39 35.1° 7.2 8 16.2° 47.2 twenty four 26.5° 16.4 40 36.0° 6.8 9 18.0° 12.0 25 27.0° 18.5 41 36.3° 7.6 10 18.9° 10.0 26 27.7° 6.5 42 36.6° 6.5 11 19.3° 8.0 27 28.8° 28.5 43 37.3° 8.5 12 20.0° 58.8 28 29.2° 13.6 44 37.7° 9.0 13 20.7° 51.9 29 29.7° 26.0 45 38.3° 13.9 14 22.3° 69.7 30 30.5° 11.9 46 39.3° 6.6 15 22.6° 20.4 31 30.8° 8.1 16 23.0° 23.5 32 31.4° 8.2

In a more preferred embodiment, the XRPD pattern of the Form Ia includes peaks at substantially the same diffraction angle (2Θ) as shown in FIG. 1 . In a preferred embodiment, the XRPD peak positions of the crystalline form Ia are substantially the same as those shown in FIG. 1 .

In a more preferred embodiment, the DSC pattern of the Form Ia includes an endothermic peak at about 108°C and an exothermic peak at about 190°C.

In a more preferred embodiment, in thermogravimetric analysis, the Form Ia has a weight loss of about 5.6% when heated to about 130°C.

In a more preferred embodiment, the DSC-TGA pattern of the crystalline form Ia includes substantially the same characteristic peaks as shown in FIG. 2 . In the most preferred embodiment, the DSC-TGA spectrum of the crystalline form Ia is substantially the same as that shown in FIG. 2 .

In a more preferred embodiment, the scanning electron micrograph of the crystalline form Ia is substantially the same as that shown in FIG. 3 .

In some embodiments, the present invention provides a method for preparing Form Ia, comprising adding Compound A to an alcoholic solvent (preferably an alcohol having 1-6 carbon atoms, including but not limited to methanol, ethanol, 1- Propanol (n-propanol), 2-propanol (isopropanol), 1-butanol, 2-butanol and tert-butanol) or ketone solvents (such as ketones with 3-6 carbon atoms, including but Not limited to acetone, butanone, methyl ethyl ketone, methyl isobutyl ketone and diethyl ketone), heating (for example, heating to 40-80 ° C, preferably 50 ° C or 60 ° C) to dissolve Compound A, Then add hydrochloric acid (concentration of hydrochloric acid is 2-15 mol/L, preferably 4 mol/L or 12 mol/L), drop to room temperature and stir, filter and dry according to the situation to obtain crystals, wherein the moles of compound A and HCl are The ratio is 1:(1-1.3).

In a preferred embodiment, the present invention provides a salt of Compound A, which is the hydrochloride salt of Compound A; Preferably, the molar ratio of compound A and hydrochloric acid is 1:1; Preferably, the hydrochloride of the compound A is crystal form Ib; The XRPD pattern of this Form Ib includes characteristic peaks at diffraction angles (2θ) of about 5.4±0.2°, 11.2±0.2° and 20.0±0.2°; Preferably included are diffraction angles (2θ) at about 5.4±0.2°, 9.5±0.2°, 11.2±0.2°, 13.6±0.2°, 20.0±0.2°, 20.8±0.2°, 24.9±0.2° and 25.5±0.2° characteristic peaks at; The best include at about 5.4±0.2°, 9.5±0.2°, 11.2±0.2°, 13.6±0.2°, 15.7±0.2°, 17.6±0.2°, 20.0±0.2°, 20.8±0.2°, 22.1±0.2°, Characteristic peaks at diffraction angles (2θ) of 23.2±0.2°, 23.6±0.2°, 24.1±0.2°, 24.6±0.2°, 24.9±0.2°, 25.5±0.2° and 30.5±0.2°.

In a more preferred embodiment, the XRPD pattern of the Form Ib includes peaks at the following diffraction angles (2θ): Peak number 2θ ( ^o ) ± 0.2 ^o I% Peak number 2θ ( ^o ) ± 0.2 ^o I% Peak number 2θ ( ^o ) ± 0.2 ^o I% 1 5.4 100 11 20.0 20.6 twenty one 27.3 1.6 2 9.5 11.1 12 20.8 10.0 twenty two 27.5 1.6 3 11.2 22.7 13 22.1 4.6 twenty three 29.5 3.7 4 12.5 2.8 14 22.6 1.6 twenty four 30.0 1.7 5 13.6 16.1 15 23.2 3.4 25 30.5 5.4 6 14.5 1.5 16 23.6 6.6 26 31.8 1.5 7 15.7 4.1 17 24.1 6.9 27 34.2 2.0 8 16.6 1.7 18 24.6 4.1 28 34.6 1.6 9 17.6 3.3 19 24.9 10.7 29 36.7 1.1 10 19.1 3.0 20 25.5 16.3

In a more preferred embodiment, the XRPD pattern of the Form Ib includes peaks at substantially the same diffraction angle (2Θ) as shown in FIG. 4 . In the best embodiment, the XRPD peak position of the crystalline form Ib is substantially the same as that shown in FIG. 4 .

In a more preferred embodiment, the DSC pattern of the Form Ib includes an exothermic peak at about 207°C.

In a more preferred embodiment, the DSC pattern of the crystalline form Ib includes substantially the same characteristic peaks as shown in FIG. 5 . In the most preferred embodiment, the DSC pattern of the crystalline form Ib is substantially the same as that shown in FIG. 5 .

In a more preferred embodiment, in thermogravimetric analysis, the Form Ib has a weight loss of about 2.6% when heated to about 167°C.

In a more preferred embodiment, the TGA pattern of the crystalline form Ib is substantially the same as that shown in FIG. 6 .

In some embodiments, the present invention provides a method for preparing Form Ib, comprising adding Compound A to an ester solvent (preferably an ester having 3-10 carbon atoms, including but not limited to ethyl acetate, propyl acetate, etc.) ester, isopropyl acetate, ethyl isopropionate, dimethyl carbonate and butyl acetate), heating (for example, heating to 40-80 ° C, preferably 50 ° C or 60 ° C) to dissolve Compound A, and then adding hydrochloric acid (concentration of hydrochloric acid is 2-15 mol/L, preferably 4 mol/L or 12 mol/L), drop to room temperature and stir, filter and dry as appropriate to obtain crystal, wherein the molar ratio of compound A and HCl is 1 :(1-1.3).

In a preferred embodiment, the present invention provides a salt of Compound A, which is the hydrochloride salt of Compound A; Preferably, the molar ratio of compound A and hydrochloric acid is 1:2; Preferably, the hydrochloride of the compound A is crystal form II; The XRPD pattern of this Form II includes characteristic peaks at diffraction angles (2θ) of about 13.3±0.2°, 14.2±0.2°, 21.9±0.2° and 27.4±0.2°; Preferably included at about 8.2±0.2°, 11.9±0.2°, 13.3±0.2°, 14.2±0.2°, 16.0±0.2°, 18.3±0.2°, 19.4±0.2°, 20.0±0.2°, 21.2±0.2°, Characteristic peaks at diffraction angles (2θ) of 21.9±0.2°, 22.9±0.2°, 24.6±0.2°, 26.6±0.2°, 27.4±0.2° and 28.0±0.2°; The best include at about 8.2±0.2°, 11.9±0.2°, 13.3±0.2°, 14.2±0.2°, 14.8±0.2°, 16.0±0.2°, 17.8±0.2°, 18.3±0.2°, 19.4±0.2°, 20.0±0.2°, 21.2±0.2°, 21.9±0.2°, 22.6±0.2°, 22.9±0.2°, 23.5±0.2°, 24.6±0.2°, 25.6±0.2°, 26.6±0.2°, 27.4±0.2°, Characteristic peaks at diffraction angles (2θ) of 28.0±0.2°, 29.7±0.2°, 31.8±0.2° and 34.0±0.2°.

In a more preferred embodiment, the XRPD pattern of the Form II includes peaks at the following diffraction angles (2θ): Peak number 2θ ( ^o ) ± 0.2 ^o I% Peak number 2θ ( ^o ) ± 0.2 ^o I% Peak number 2θ ( ^o ) ± 0.2 ^o I% 1 7.2° 15.1 18 21.6° 19.2 35 29.4° 21.4 2 8.2° 32.7 19 21.9° 100 36 29.7° 23.6 3 9.1° 15.0 20 22.6° 25.5 37 30.0° 13.3 4 10.5° 16.2 twenty one 22.9° 34.5 38 30.7° 13.1 5 11.9° 30.3 twenty two 23.5° 29.4 39 30.9° 13.4 6 13.3° 67.9 twenty three 23.8° 25.3 40 31.8° 28.1 7 14.2° 51.1 twenty four 24.0° 18.9 41 32.5° 14.6 8 14.8° 18.5 25 24.6° 35.0 42 32.9° 14.4 9 15.6° 10.4 26 24.9° 14.9 43 33.4° 10.6 10 16.0° 32.3 27 25.6° 20.4 44 34.0° 23.4 11 16.6° 9.5 28 26.3° 26.3 45 34.6° 10.2 12 17.8° 15.0 29 26.6° 49.3 46 35.0° 12.2 13 18.3° 33.8 30 27.0° 33.6 47 35.7° 11.8 14 19.4° 44.8 31 27.4° 72.9 48 36.1° 11.6 15 20.0° 36.1 32 28.0° 32.4 49 37.0° 13.4 16 20.6° 14.1 33 28.4° 14.9 50 38.6° 8.8 17 21.2° 35.4 34 28.7° 12.7 51 39.5° 7.8

In a more preferred embodiment, the XRPD pattern of the Form II includes peaks at substantially the same diffraction angle (2Θ) as shown in FIG. 7 . In a preferred embodiment, the XRPD peak positions of the Form II are substantially the same as those shown in FIG. 7 .

In a more preferred embodiment, the DSC pattern of the Form II includes an endothermic peak at about 40°C.

In a more preferred embodiment, in thermogravimetric analysis, the Form II has a weight loss of about 0.9% when heated to about 180°C.

In a more preferred embodiment, the DSC-TGA pattern of the crystal form II includes substantially the same characteristic peaks as shown in FIG. 8 . In the best embodiment, the DSC-TGA pattern of the crystal form II is substantially the same as that shown in FIG. 8 .

In some embodiments, the present invention provides a method for preparing Form II comprising adding Compound A to an alcoholic solvent (preferably an alcohol having 1-6 carbon atoms, including but not limited to methanol, ethanol, 1- Propanol (n-propanol), 2-propanol (isopropanol), 1-butanol, 2-butanol and tert-butanol), heated (for example, heated to 40-80°C, preferably 50°C or 60°C ) make compound A dissolve, then add hydrochloric acid (concentration of hydrochloric acid is 2-15 mol/L, preferably 4 mol/L or 12 mol/L), be down to room temperature and stir, filter and dry according to the situation to obtain crystal, wherein compound The molar ratio of A and HCl was 1:(2-2.5).

In a preferred embodiment, the present invention provides a salt of Compound A, which is a citrate salt of Compound A; Preferably, the molar ratio of compound A and citric acid is 1:0.5; Preferably, the citrate of the compound A is crystal form III; The XRPD pattern of Form III includes characteristic peaks at diffraction angles (2θ) of about 6.9±0.2°, 10.8±0.2°, 14.6±0.2°, 20.3±0.2° and 22.5±0.2°; It preferably includes diffraction angles (2θ) at about 6.9±0.2°, 10.8±0.2°, 14.6±0.2°, 16.3±0.2°, 20.3±0.2°, 22.5±0.2°, 23.4±0.2°, and 26.6±0.2° characteristic peaks at; The best include at about 6.9±0.2°, 10.8±0.2°, 12.7±0.2°, 14.6±0.2°, 16.3±0.2°, 17.6±0.2°, 18.1±0.2°, 20.3±0.2°, 21.4±0.2°, Characteristic peaks at diffraction angles (2θ) of 22.5±0.2°, 23.4±0.2°, 24.2±0.2°, 25.5±0.2°, 26.0±0.2°, 26.6±0.2° and 27.1±0.2°.

In a more preferred embodiment, the XRPD pattern of the Form III includes peaks at the following diffraction angles (2θ): Peak number 2θ ( ^o ) ± 0.2 ^o I% Peak number 2θ ( ^o ) ± 0.2 ^o I% Peak number 2θ ( ^o ) ± 0.2 ^o I% 1 6.9° 100 10 16.3° 29.2 19 25.5° 16.8 2 10.2° 13.3 11 17.6° 10.9 20 26.0° 18.9 3 10.8° 87.2 12 18.1° 15.1 twenty one 26.6° 31.5 4 12.4° 15.0 13 18.7° 7.9 twenty two 27.1° 12.9 5 12.7° 22.1 14 20.3° 58.0 twenty three 30.7° 8.6 6 13.9° 11.3 15 21.4° 19.9 twenty four 34.0° 7.3 7 14.6° 46.3 16 22.5° 48.1 25 35.1° 9.4 8 14.8° 26.1 17 23.4° 39.4 26 37.1° 8.9 9 15.1° 13.0 18 24.2° 18.1 27 38.8° 7.6

In a more preferred embodiment, the XRPD pattern of the Form III includes peaks at substantially the same diffraction angle (2Θ) as shown in FIG. 9 . In the best embodiment, the XRPD peak position of the crystal form III is substantially the same as that shown in FIG. 9 .

In a more preferred embodiment, the DSC pattern of the Form III includes an endothermic peak at about 117°C.

In a more preferred embodiment, in thermogravimetric analysis, the Form III has a weight loss of about 2.9% when heated to about 150°C.

In a more preferred embodiment, the DSC-TGA pattern of the crystal form III includes substantially the same characteristic peaks as shown in FIG. 10 . In the most preferred embodiment, the DSC-TGA pattern of the crystal form III is substantially the same as that shown in FIG. 10 .

In a more preferred embodiment, the scanning electron microscope photograph of Form III is substantially the same as that shown in FIG. 11 .

In some embodiments, the present invention provides a method for preparing Form III comprising adding Compound A to an alcoholic solvent (preferably an alcohol having 1-6 carbon atoms, including but not limited to methanol, ethanol, 1- Propanol (n-propanol), 2-propanol (isopropanol), 1-butanol, 2-butanol and tert-butanol), heated (for example, heated to 40-80°C, preferably 50°C or 60°C ) to dissolve compound A, then add citric acid (preferably a methanol or ethanol solution of citric acid), drop to room temperature and stir, filter and dry as appropriate to obtain crystals, wherein the molar ratio of compound A and citric acid is 1: (1-1.3).

In a preferred embodiment, the present invention provides a salt of Compound A, which is a sulfate salt of Compound A; Preferably, the molar ratio of compound A and sulfuric acid is 1:0.5; Preferably, the sulfate of the compound A is crystal form IV; The XRPD pattern of Form IV includes characteristic peaks at diffraction angles (2θ) of about 8.0±0.2°, 11.2±0.2°, 20.9±0.2°, 21.8±0.2° and 26.3±0.2°; It preferably includes diffraction angles (2θ) at about 8.0±0.2°, 10.5±0.2°, 11.2±0.2°, 20.9±0.2°, 21.8±0.2°, 22.5±0.2°, 23.8±0.2° and 26.3±0.2° characteristic peaks at; Optimum includes at about 8.0±0.2°, 10.5±0.2°, 11.2±0.2°, 13.2±0.2°, 15.3±0.2°, 15.9±0.2°, 16.8±0.2°, 19.0±0.2°, 20.9±0.2°, Diffraction angles (2θ) of 21.8±0.2°, 22.5±0.2°, 23.8±0.2°, 24.9±0.2°, 26.3±0.2°, 28.3±0.2°, 29.1±0.2°, 30.1±0.2° and 37.9±0.2° characteristic peaks at .

In a more preferred embodiment, the XRPD pattern of the Form IV includes peaks at the following diffraction angles (2θ): Peak number 2θ ( ^o ) ± 0.2 ^o I% Peak number 2θ ( ^o ) ± 0.2 ^o I% Peak number 2θ ( ^o ) ± 0.2 ^o I% 1 8.0° 85.1 10 21.8° 100 19 31.0° 8.7 2 10.5° 33.4 11 22.5° 38.7 20 31.9° 10.3 3 11.2° 65.7 12 23.5° 18.2 twenty one 32.2° 9.4 4 13.2° 15.9 13 23.8° 37.3 twenty two 33.9° 11.3 5 15.3° 16.9 14 24.9° 30.0 twenty three 35.6° 6.5 6 15.9° 14.7 15 26.3° 41.2 twenty four 37.3° 7.1 7 16.8° 13.7 16 28.3° 14.8 25 37.9° 12.0 8 19.0° 13.7 17 29.1° 14.1 26 38.7° 6.2 9 20.9° 39.9 18 30.1° 29.0

In a more preferred embodiment, the XRPD pattern of the Form IV includes peaks at substantially the same diffraction angle (2Θ) as shown in FIG. 12 . In a preferred embodiment, the XRPD peak positions of the Form IV are substantially the same as those shown in FIG. 12 .

In a more preferred embodiment, the DSC pattern of the Form IV includes an endothermic peak at about 41°C.

In a more preferred embodiment, in thermogravimetric analysis, the Form IV has a weight loss of about 2.1% when heated to about 150°C.

In a more preferred embodiment, the DSC-TGA pattern of the crystal form IV includes substantially the same characteristic peaks as shown in FIG. 13 . In a preferred embodiment, the DSC-TGA pattern of the Form IV is substantially the same as that shown in FIG. 13 .

In some embodiments, the present invention provides a method for preparing Form IV comprising adding Compound A to an alcoholic solvent (preferably an alcohol having 1-6 carbon atoms, including but not limited to methanol, ethanol, 1- Propanol (n-propanol), 2-propanol (isopropanol), 1-butanol, 2-butanol and tert-butanol), heated (for example, heated to 40-80°C, preferably 55°C or 60°C ) to dissolve compound A, then add sulfuric acid (such as a methanol or ethanol solution of sulfuric acid), drop to room temperature and stir, filter and dry as appropriate to obtain crystals, wherein the molar ratio of compound A and sulfuric acid is 1:(0.4-0.6 ), preferably 1:0.5.

In a preferred embodiment, the present invention provides a salt of Compound A, which is a sulfate salt of Compound A; Preferably, the molar ratio of compound A and sulfuric acid is 1:1; Preferably, the sulfate of the compound A is crystal form V; The XRPD pattern of Form V includes characteristic peaks at diffraction angles (2θ) of about 7.9±0.2°, 11.2±0.2°, 20.3±0.2°, 21.7±0.2° and 26.3±0.2°; It preferably includes diffraction angles (2θ) at about 7.9±0.2°, 11.2±0.2°, 20.3±0.2°, 21.7±0.2°, 22.5±0.2°, 23.7±0.2°, 24.8±0.2°, and 26.3±0.2° characteristic peaks at; The best include at about 7.9±0.2°, 10.4±0.2°, 11.2±0.2°, 13.1±0.2°, 15.1±0.2°, 15.7±0.2°, 15.9±0.2°, 16.6±0.2°, 18.9±0.2°, 20.3±0.2°, 21.0±0.2°, 21.7±0.2°, 22.5±0.2°, 23.7±0.2°, 24.3±0.2°, 24.8±0.2°, 26.3±0.2°, 28.2±0.2°, 29.1±0.2°, Characteristic peaks at diffraction angles (2Θ) of 30.1 ± 0.2° and 37.9 ± 0.2°.

In a more preferred embodiment, the XRPD pattern of the Form V includes peaks at the following diffraction angles (2θ): Peak number 2θ ( ^o ) ± 0.2 ^o I% Peak number 2θ ( ^o ) ± 0.2 ^o I% Peak number 2θ ( ^o ) ± 0.2 ^o I% 1 7.9° 100 11 20.3° 35.8 twenty one 29.1° 10.6 2 10.4° 18.4 12 21.0° 14.6 twenty two 30.1° 26.0 3 11.2° 50.6 13 21.7° 94.8 twenty three 31.8° 8.9 4 12.7° 6.5 14 22.5° 28.1 twenty four 32.3° 11.2 5 13.1° 10.4 15 23.3° 14.2 25 34.0° 8.7 6 15.1° 10.2 16 23.7° 22.7 26 35.5° 7.1 7 15.7° 11.0 17 24.3° 14.2 27 37.3° 5.6 8 15.9° 10.5 18 24.8° 24.3 28 37.9° 10.3 9 16.6° 15.9 19 26.3° 39.7 10 18.9° 10.0 20 28.2° 14.7

In a more preferred embodiment, the XRPD pattern of the Form V includes peaks at substantially the same diffraction angle (2Θ) as shown in FIG. 14 . In a preferred embodiment, the XRPD peak positions of the Form V are substantially the same as those shown in FIG. 14 .

In a more preferred embodiment, the DSC pattern of the Form V includes an endothermic peak at about 35°C.

In a more preferred embodiment, in thermogravimetric analysis, the Form V has a weight loss of about 0.8% when heated to about 150°C.

In a more preferred embodiment, the DSC-TGA pattern of the crystal form V includes substantially the same characteristic peaks as shown in FIG. 15 . In the most preferred embodiment, the DSC-TGA pattern of the Form V is substantially the same as that shown in FIG. 15 .

In some embodiments, the present invention provides a method for preparing Form V, comprising adding Compound A to an alcoholic solvent (preferably an alcohol having 1-6 carbon atoms, including but not limited to methanol, ethanol, 1- Propanol (n-propanol), 2-propanol (isopropanol), 1-butanol, 2-butanol and tert-butanol), heated (for example, heated to 40-80°C, preferably 55°C or 60°C ) to dissolve compound A, then add sulfuric acid (such as a methanol or ethanol solution of sulfuric acid), drop to room temperature and stir, filter and dry as appropriate to obtain crystals, wherein the molar ratio of compound A and sulfuric acid is 1:(1-1.3 ), preferably about 1:1.

In a preferred embodiment, the present invention provides a salt of Compound A, which is a p-toluenesulfonate salt of Compound A; Preferably, the molar ratio of compound A and p-toluenesulfonic acid is 1:1; Preferably, the p-toluenesulfonate of the compound A is crystal form VI; The XRPD pattern of Form VI includes characteristic peaks at diffraction angles (2θ) of about 9.2±0.2°, 10.8±0.2°, 18.0±0.2° and 19.5±0.2°; Preferably included at about 9.2±0.2°, 10.8±0.2°, 17.7±0.2°, 18.0±0.2°, 18.5±0.2°, 19.5±0.2°, 20.4±0.2°, 21.7±0.2°, 21.9±0.2°, Characteristic peaks at diffraction angles (2θ) of 23.6±0.2° and 28.6±0.2°; The best include at about 9.2±0.2°, 10.8±0.2°, 14.9±0.2°, 15.4±0.2°, 17.7±0.2°, 18.0±0.2°, 18.5±0.2°, 19.5±0.2°, 20.4±0.2°, Diffraction angles (2θ) of 21.2±0.2°, 21.7±0.2°, 21.9±0.2°, 23.6±0.2°, 24.5±0.2°, 26.2±0.2°, 28.6±0.2°, 32.1±0.2° and 32.7±0.2° characteristic peaks at .

In a more preferred embodiment, the XRPD pattern of the Form VI includes peaks at the following diffraction angles (2θ): Peak number 2θ ( ^o ) ± 0.2 ^o I% Peak number 2θ ( ^o ) ± 0.2 ^o I% Peak number 2θ ( ^o ) ± 0.2 ^o I% 1 5.1° 12.6 14 21.7° 35.8 27 30.8° 6.5 2 9.2° 41.7 15 21.9° 34.8 28 31.6° 6.5 3 10.8° 51.5 16 23.1° 11.0 29 32.1° 10.1 4 14.9° 25.7 17 23.6° 33.9 30 32.7° 11.0 5 15.4° 25.9 18 24.0° 14.9 31 33.3° 7.2 6 15.7° 8.8 19 24.5° 26.6 32 33.7° 6.5 7 16.3° 8.8 20 25.8° 10.0 33 34.6° 4.3 8 17.7° 34.1 twenty one 26.2° 23.0 34 35.9° 5.4 9 18.0° 46.5 twenty two 27.6° 10.7 35 36.6° 5.6 10 18.5° 28.5 twenty three 28.0° 12.6 36 37.9° 6.5 11 19.5° 100 twenty four 28.6° 45.0 37 39.0° 5.0 12 20.4° 28.2 25 29.6° 8.1 38 39.6° 6.5 13 21.2° 25.5 26 30.4° 7.2

In a more preferred embodiment, the XRPD pattern of the Form VI includes peaks at substantially the same diffraction angle (2Θ) as shown in FIG. 16 . In a preferred embodiment, the XRPD peak positions of the Form VI are substantially the same as those shown in FIG. 16 .

In a more preferred embodiment, the DSC pattern of the Form VI includes an endothermic peak at about 36°C.

In a more preferred embodiment, in thermogravimetric analysis, the Form VI has a weight loss of about 3% when heated to about 180°C.

In a more preferred embodiment, the DSC-TGA pattern of the crystal form VI includes substantially the same characteristic peaks as shown in FIG. 17 . In the most preferred embodiment, the DSC-TGA spectrum of the crystal form VI is substantially the same as that shown in FIG. 17 .

In some embodiments, the present invention provides a method of preparing Form VI comprising adding Compound A to a ketone-based solvent (eg, a ketone having 3-6 carbon atoms, including but not limited to acetone, butanone, methyl ethyl ketone, methyl isobutyl ketone and diethyl ketone), heating (for example, heating to 40-80 ° C, preferably 50 ° C or 60 ° C) to dissolve compound A, and then adding p-toluenesulfonic acid (for example, p-toluenesulfonic acid). The methanol or ethanol solution of toluenesulfonic acid) to obtain the reactant solution, the reactant solution is concentrated to dryness as the case may be and the above-mentioned ketone solvent is added again, the obtained solution is lowered to room temperature and stirred, and filtered to obtain crystals, wherein compound A and p- The molar ratio of toluenesulfonic acid is 1:(1-1.3), preferably about 1:1.

In a preferred embodiment, the present invention provides a salt of Compound A, which is a mesylate salt of Compound A; Preferably, the molar ratio of compound A and methanesulfonic acid is 1:1; Preferably, the mesylate of compound A is crystal form VII; The XRPD pattern of the crystal form VII includes characteristic peaks at diffraction angles (2θ) of about 7.7±0.2°, 10.5±0.2°, 19.0±0.2°, 20.1±0.2° and 20.5±0.2°; Preferably included at about 7.7±0.2°, 10.5±0.2°, 16.2±0.2°, 16.8±0.2°, 19.0±0.2°, 19.9±0.2°, 20.1±0.2°, 20.5±0.2°, 21.0±0.2°, Characteristic peaks at diffraction angles (2θ) of 22.6±0.2°, 24.0±0.2°, 25.5±0.2° and 26.5±0.2°; Optimum includes at about 6.0±0.2°, 7.7±0.2°, 10.5±0.2°, 11.0±0.2°, 12.3±0.2°, 13.5±0.2°, 14.0±0.2°, 14.3±0.2°, 14.9±0.2°, 15.5±0.2°, 16.2±0.2°, 16.8±0.2°, 19.0±0.2°, 19.9±0.2°, 20.1±0.2°, 20.5±0.2°, 21.0±0.2°, 21.4±0.2°, 22.6±0.2°, Characteristic peaks at diffraction angles (2θ) of 23.2±0.2°, 24.0±0.2°, 24.9±0.2°, 25.5±0.2°, 25.8±0.2°, 26.5±0.2°, 27.6±0.2° and 29.6±0.2°.

In a more preferred embodiment, the XRPD pattern of the Form VII includes peaks at the following diffraction angles (2θ): Peak number 2θ ( ^o ) ± 0.2 ^o I% Peak number 2θ ( ^o ) ± 0.2 ^o I% Peak number 2θ ( ^o ) ± 0.2 ^o I% 1 6.0° 23.4 16 17.8° 9.6 31 25.8° 23.0 2 7.7° 51.5 17 18.2° 10.2 32 26.5° 31.7 3 10.0° 14.3 18 19.0° 62.0 33 27.6° 16.0 4 10.5° 81.9 19 19.9° 45.4 34 28.2° 11.7 5 11.0° 22.2 20 20.1° 100 35 29.1° 13.6 6 12.3° 23.0 twenty one 20.5° 73.4 36 29.6° 18.4 7 12.6° 13.6 twenty two 21.0° 40.7 37 30.0° 9.5 8 13.5° 18.7 twenty three 21.4° 18.8 38 30.5° 10.6 9 14.0° 26.2 twenty four 21.9° 10.6 39 31.9° 12.2 10 14.3° 20.3 25 22.6° 37.8 40 32.6° 7.1 11 14.9° 17.3 26 23.2° 33.0 41 33.2° 10.3 12 15.5° 21.4 27 23.4° 23.8 42 34.4° 9.6 13 15.8° 14.1 28 24.0° 33.2 43 35.2° 8.3 14 16.2° 39.6 29 24.9° 22.0 44 35.9° 6.9 15 16.8° 33.5 30 25.5° 29.2 45 37.4° 8.5

In a more preferred embodiment, the XRPD pattern of the Form VII includes peaks at substantially the same diffraction angle (2θ) as shown in FIG. 18 . In the best embodiment, the XRPD peak position of the crystal form VII is substantially the same as that shown in FIG. 18 .

In a more preferred embodiment, the DSC pattern of the Form VII includes an endothermic peak at about 99°C.

In a more preferred embodiment, in thermogravimetric analysis, the Form VII has a weight loss of about 0.9% when heated to about 150°C.

In a more preferred embodiment, the DSC-TGA spectrum of the crystal form VII includes substantially the same characteristic peaks as shown in FIG. 19 . In the best embodiment, the DSC-TGA spectrum of the crystal form VII is substantially the same as that shown in FIG. 19 .

In a more preferred embodiment, the scanning electron micrograph of the Form VII is substantially the same as that shown in FIG. 20 .

In some embodiments, the present invention provides methods of preparing Form VII comprising adding Compound A to an ethereal solvent (eg, an ether having 3-10 carbon atoms, preferably a cyclic ether, eg, a furan (including tetrahydrofuran) and dioxane, preferably tetrahydrofuran, 2-methyltetrahydrofuran or dioxane), heating (for example, heating to 40-80°C, preferably 50°C or 60°C) to dissolve Compound A , then add methanesulfonic acid, drop to room temperature and stir, and filter to obtain crystals, wherein the molar ratio of compound A and methanesulfonic acid is 1:(1-1.3), preferably about 1:1.

In a preferred embodiment, the present invention provides a salt of Compound A, which is a mesylate salt of Compound A; Preferably, the molar ratio of compound A and methanesulfonic acid is 1:2; Preferably, the mesylate of compound A is crystal form VIII; The XRPD pattern of this Form VIII includes diffraction angles (2θ) at about 11.0±0.2°, 12.2±0.2°, 13.4±0.2°, 19.9±0.2°, 20.2±0.2°, 21.4±0.2° and 25.8±0.2° characteristic peaks at; Preferably included at about 3.2±0.2°, 6.0±0.2°, 11.0±0.2°, 12.2±0.2°, 13.4±0.2°, 19.9±0.2°, 20.2±0.2°, 21.0±0.2°, 21.4±0.2°, Characteristic peaks at diffraction angles (2θ) of 23.0±0.2°, 23.4±0.2°, 24.9±0.2° and 25.8±0.2°; The best include at about 3.2±0.2°, 6.0±0.2°, 9.4±0.2°, 11.0±0.2°, 12.2±0.2°, 13.4±0.2°, 14.9±0.2°, 15.5±0.2°, 15.7±0.2°, 17.7±0.2°, 18.1±0.2°, 18.9±0.2°, 19.9±0.2°, 20.2±0.2°, 21.0±0.2°, 21.4±0.2°, 21.9±0.2°, 22.4±0.2°, 23.0±0.2°, 23.4±0.2°, 23.9±0.2°, 24.9±0.2°, 25.2±0.2°, 25.8±0.2°, 26.5±0.2°, 27.4±0.2°, 28.9±0.2°, 30.8±0.2° and 31.5±0.2° Characteristic peak at diffraction angle (2θ).

In a more preferred embodiment, the XRPD pattern of the Form VIII includes peaks at the following diffraction angles (2θ): Peak number 2θ ( ^o ) ± 0.2 ^o I% Peak number 2θ ( ^o ) ± 0.2 ^o I% Peak number 2θ ( ^o ) ± 0.2 ^o I% 1 3.2° 41.4 16 20.2° 100 31 27.4° 24.0 2 6.0° 35.5 17 21.0° 61.2 32 28.3° 15.3 3 9.4° 19.6 18 21.4° 79.6 33 28.7° 24.8 4 11.0° 72.1 19 21.9° 23.9 34 28.9° 32.0 5 12.2° 84.1 20 22.4° 29.7 35 29.6° 14.8 6 13.4° 67.7 twenty one 23.0° 62.7 36 30.2° 18.9 7 14.9° 17.8 twenty two 23.4° 55.4 37 30.8° 23.8 8 15.5° 27.6 twenty three 23.9° 28.5 38 31.1° 16.1 9 15.7° 28.3 twenty four 24.3° 17.1 39 31.5° 23.4 10 17.1° 11.0 25 24.6° 22.3 40 33.1° 10.2 11 17.7° 28.8 26 24.9° 38.9 41 33.2° 9.4 12 18.1° 29.5 27 25.2° 29.7 42 34.7° 12.8 13 18.9° 14.9 28 25.8° 99.5 43 35.2° 14.1 14 19.6° 19.3 29 26.5° 19.1 44 37.9° 12.2 15 19.9° 69.8 30 27.1° 14.8

In a more preferred embodiment, the XRPD pattern of the Form VIII includes peaks at substantially the same diffraction angle (2Θ) as shown in FIG. 21 . In the best embodiment, the XRPD peak position of the crystal form VIII is substantially the same as that shown in FIG. 21 .

In a more preferred embodiment, the DSC pattern of the Form VIII includes an endothermic peak at about 101°C.

In a more preferred embodiment, in thermogravimetric analysis, the Form VIII has a weight loss of about 7.5% when heated to about 150°C.

In a more preferred embodiment, the DSC-TGA pattern of the crystal form VIII includes substantially the same characteristic peaks as shown in FIG. 22 . In the most preferred embodiment, the DSC-TGA spectrum of the crystal form VIII is substantially the same as that shown in FIG. 22 .

In a more preferred embodiment, the scanning electron micrograph of the crystal form VIII is substantially the same as that shown in FIG. 23 .

In some embodiments, the present invention provides a method of preparing Form VIII comprising adding Compound A to an ethereal solvent (eg, an ether having 3-10 carbon atoms, preferably a cyclic ether, such as a furan (including tetrahydrofuran) and dioxane, preferably tetrahydrofuran, 2-methyltetrahydrofuran or dioxane), heating (for example, heating to 40-80°C, preferably 50°C or 60°C) to dissolve Compound A , then add methanesulfonic acid, drop to room temperature and stir, and filter to obtain crystals, wherein the molar ratio of compound A and methanesulfonic acid is 1:(2-2.5).

In a preferred embodiment, the present invention provides a salt of Compound A, which is a phosphate of Compound A; Preferably, the molar ratio of compound A and phosphoric acid is 1:1; Preferably, the phosphate of the compound A is crystal form IX; The XRPD pattern of Form IX includes characteristic peaks at diffraction angles (2θ) of about 7.0±0.2°, 10.7±0.2°, 14.6±0.2° and 26.7±0.2°; It preferably includes diffraction angles (2θ) at about 7.0±0.2°, 10.7±0.2°, 14.6±0.2°, 15.3±0.2°, 18.4±0.2°, 22.3±0.2°, 23.4±0.2° and 26.7±0.2° characteristic peaks at; The best include at about 7.0±0.2°, 10.7±0.2°, 14.0±0.2°, 14.6±0.2°, 15.3±0.2°, 16.2±0.2°, 18.4±0.2°, 20.3±0.2°, 21.5±0.2°, Characteristic peaks at diffraction angles (2θ) of 22.3±0.2°, 23.4±0.2°, 24.3±0.2°, 25.7±0.2°, 26.7±0.2° and 29.5±0.2°.

In a more preferred embodiment, the XRPD pattern of the Form IX includes peaks at the following diffraction angles (2θ): Peak number 2θ ( ^o ) ± 0.2 ^o I% Peak number 2θ ( ^o ) ± 0.2 ^o I% Peak number 2θ ( ^o ) ± 0.2 ^o I% 1 7.0° 100 9 17.3° 7.1 17 25.7° 14.6 2 10.2° 8.4 10 18.4° 20.9 18 26.7° 33.9 3 10.7° 46.8 11 20.3° 18.8 19 28.2° 6.8 4 12.3° 7.3 12 21.5° 15.2 20 29.5° 9.1 5 14.0° 14.5 13 22.3° 30.7 twenty one 30.1° 9.0 6 14.6° 47.9 14 23.4° 27.6 twenty two 30.9° 6.6 7 15.3° 20.1 15 24.3° 18.1 twenty three 32.6° 5.4 8 16.2° 11.5 16 24.9° 11.0 twenty four 35.1° 6.2

In a more preferred embodiment, the XRPD pattern of the Form IX includes peaks at substantially the same diffraction angle (2Θ) as shown in FIG. 24 . In a preferred embodiment, the XRPD peak positions of the Form IX are substantially the same as those shown in FIG. 24 .

In a more preferred embodiment, the DSC pattern of the Form IX includes an endothermic peak at about 100°C.

In a more preferred embodiment, in thermogravimetric analysis, the Form IX has about 1.2% weight loss when heated to about 50°C and about 4.6% weight loss at about 50-120°C.

In a more preferred embodiment, the DSC-TGA pattern of the crystalline form IX includes substantially the same characteristic peaks as shown in FIG. 25 . In a preferred embodiment, the DSC-TGA pattern of the Form IX is substantially the same as that shown in FIG. 25 .

In a more preferred embodiment, the scanning electron micrograph of the Form IX is substantially the same as that shown in FIG. 26 .

In some embodiments, the present invention provides a method of preparing Form IX comprising adding Compound A to an alcoholic solvent (preferably an alcohol having 1-6 carbon atoms, including but not limited to methanol, ethanol, 1- Propanol (n-propanol), 2-propanol (isopropanol), 1-butanol, 2-butanol and tert-butanol), heated (for example, heated to 40-80°C, preferably 55°C or 60°C ) to dissolve compound A, then add phosphoric acid, drop to room temperature and stir, and filter to obtain crystals, wherein the molar ratio of compound A and phosphoric acid is 1:(1-1.3), preferably about 1:1.

In a preferred embodiment, the present invention provides a salt of Compound A, which is a maleate salt of Compound A; Preferably, the molar ratio of compound A and maleic acid is 1:1; Preferably, the maleate of compound A is crystal form X; The XRPD pattern of Form X includes characteristic peaks at diffraction angles (2θ) of about 5.4±0.2°, 5.8±0.2°, 13.7±0.2° and 17.1±0.2°; Preferably included at about 5.4±0.2°, 5.8±0.2°, 8.9±0.2°, 10.0±0.2°, 13.7±0.2°, 16.0±0.2°, 17.1±0.2°, 21.7±0.2° and 21.9±0.2° Characteristic peaks at the diffraction angle (2θ); The best include at about 5.4±0.2°, 5.8±0.2°, 8.9±0.2°, 10.0±0.2°, 13.7±0.2°, 16.0±0.2°, 17.1±0.2°, 21.7±0.2°, 21.9±0.2°, Characteristic peaks at diffraction angles (2Θ) of 24.1 ± 0.2°, 25.8 ± 0.2° and 27.6 ± 0.2°.

In a more preferred embodiment, the XRPD pattern of the Form X includes peaks at the following diffraction angles (2θ): Peak number 2θ ( ^o ) ± 0.2 ^o I% Peak number 2θ ( ^o ) ± 0.2 ^o I% Peak number 2θ ( ^o ) ± 0.2 ^o I% 1 5.4° 100 12 17.9° 2.4 twenty three 25.1° 3.7 2 5.8° 13.5 13 18.6° 4.5 twenty four 25.8° 8.8 3 8.5° 2.6 14 19.2° 4.2 25 26.7° 4.2 4 8.9° 11.3 15 19.8° 6.5 26 27.6° 9.3 5 10.0° 13.0 16 20.7° 3.5 27 28.9° 2.0 6 10.8° 3.4 17 21.7° 13.5 28 31.7° 3.3 7 13.7° 19.3 18 21.9° 14.0 29 33.9° 2.4 8 14.3° 3.3 19 22.2° 5.9 30 34.8° 1.5 9 15.0° 2.7 20 22.7° 4.2 31 35.8° 1.6 10 16.0° 10.2 twenty one 23.4° 4.3 32 38.8° 1.6 11 17.1° 13.5 twenty two 24.1° 7.3

In a more preferred embodiment, the XRPD pattern of the Form X includes peaks at substantially the same diffraction angle (2θ) as shown in FIG. 27 . In the best embodiment, the XRPD peak position of the Form X is substantially the same as that shown in FIG. 27 .

In a more preferred embodiment, the DSC pattern of the Form X includes an endothermic peak at about 29°C.

In a more preferred embodiment, in thermogravimetric analysis, the Form X has a weight loss of about 1% when heated to about 100°C.

In a more preferred embodiment, the DSC-TGA pattern of the crystal form X includes substantially the same characteristic peaks as shown in FIG. 28 . In the most preferred embodiment, the DSC-TGA pattern of the Form X is substantially the same as that shown in FIG. 28 .

In a more preferred embodiment, the scanning electron micrograph of the Form X is substantially the same as that shown in FIG. 29 .

In some embodiments, the present invention provides a method for preparing Form X, comprising adding Compound A to an alcoholic solvent (preferably an alcohol having 1-6 carbon atoms, including but not limited to methanol, ethanol, 1- Propanol (n-propanol), 2-propanol (isopropanol), 1-butanol, 2-butanol and tert-butanol), heated (for example, heated to 40-80°C, preferably 55°C or 60°C ) to dissolve compound A, then add maleic acid (preferably a methanol or ethanol solution of maleic acid), drop to room temperature and stir, filter and dry as appropriate to obtain crystals, wherein the molar ratio of compound A and maleic acid is It is 1:(1-1.3), preferably about 1:1.

In a preferred embodiment, the present invention provides a salt of Compound A, which is the L-tartrate salt of Compound A; Preferably, the molar ratio of compound A and L-tartaric acid is 1:1; Preferably, the L-tartrate of compound A is crystal form XI; The XRPD pattern of the crystalline form XI includes characteristic peaks at diffraction angles (2θ) of about 6.5±0.2°, 14.3±0.2°, 20.8±0.2°, 21.5±0.2° and 25.2±0.2°; Preferably included at about 6.5±0.2°, 10.9±0.2°, 12.6±0.2°, 14.3±0.2°, 16.1±0.2°, 17.3±0.2°, 18.0±0.2°, 20.8±0.2°, 21.5±0.2°, Characteristic peaks at diffraction angles (2θ) of 22.5±0.2° and 25.2±0.2°; The best include at about 6.5±0.2°, 10.3±0.2°, 10.9±0.2°, 12.6±0.2°, 14.3±0.2°, 15.2±0.2°, 16.1±0.2°, 17.3±0.2°, 18.0±0.2°, 19.4±0.2°, 20.8±0.2°, 21.5±0.2°, 22.0±0.2°, 22.5±0.2°, 23.4±0.2°, 23.8±0.2°, 24.2±0.2°, 24.8±0.2°, 25.2±0.2°, Characteristic peaks at diffraction angles (2θ) of 25.8±0.2°, 26.7±0.2°, 27.8±0.2°, 28.8±0.2°, 30.1±0.2°, 31.4±0.2°, 33.8±0.2° and 35.2±0.2°.

In a more preferred embodiment, the XRPD pattern of the Form XI includes peaks at the following diffraction angles (2θ): Peak number 2θ ( ^o ) ± 0.2 ^o I% Peak number 2θ ( ^o ) ± 0.2 ^o I% Peak number 2θ ( ^o ) ± 0.2 ^o I% 1 6.5° 76.8 15 22.5° 27.1 29 31.4° 13.0 2 10.3° 12.3 16 23.4° 21.4 30 31.9° 8.1 3 10.9° 31.4 17 23.8° 12.6 31 32.5° 9.5 4 12.6° 27.4 18 24.2° 18.6 32 32.9° 7.2 5 14.3° 45.0 19 24.5° 15.7 33 33.8° 17.1 6 14.9° 10.1 20 24.8° 20.9 34 34.7° 6.8 7 15.2° 14.9 twenty one 25.2° 40.4 35 35.2° 9.6 8 16.1° 25.3 twenty two 25.8° 10.3 36 35.9° 7.7 9 17.3° 30.1 twenty three 26.7° 11.3 37 36.2° 5.3 10 18.0° 36.9 twenty four 27.2° 7.0 38 36.8° 5.1 11 19.4° 19.7 25 27.8° 12.6 39 37.8° 7.0 12 20.8° 43.1 26 28.8° 11.9 40 38.2° 7.0 13 21.5° 100 27 29.3° 9.5 41 39.3° 8.9 14 22.0° 18.8 28 30.1° 12.0

In a more preferred embodiment, the XRPD pattern of the Form XI includes peaks at substantially the same diffraction angle (2Θ) as shown in FIG. 30 . In a preferred embodiment, the XRPD peak positions of the Form XI are substantially the same as those shown in FIG. 30 .

In a more preferred embodiment, the DSC pattern of the crystal form XI does not contain endothermic peaks.

In a more preferred embodiment, in thermogravimetric analysis, the Form XI has a weight loss of about 0.7% when heated to about 170°C.

In a more preferred embodiment, the DSC-TGA spectrum of the crystal form XI is substantially the same as that shown in FIG. 31 .

In a more preferred embodiment, the scanning electron micrograph of the Form XI is substantially the same as that shown in FIG. 32 .

In some embodiments, the present invention provides a method for preparing Form XI, comprising adding Compound A to an alcoholic solvent (preferably an alcohol having 1-6 carbon atoms, including but not limited to methanol, ethanol, 1- Propanol (n-propanol), 2-propanol (isopropanol), 1-butanol, 2-butanol and tert-butanol), heated (for example, heated to 40-80°C, preferably 55°C or 60°C ) to dissolve compound A, then add L-tartaric acid (preferably the methanol or ethanol solution of L-tartaric acid), drop to room temperature and stir, filter and dry as appropriate to obtain crystals, wherein the molar ratio of compound A and L-tartaric acid is It is 1:(1-1.3), preferably about 1:1.

In a preferred embodiment, the present invention provides a salt of Compound A, which is a fumarate salt of Compound A; Preferably, the molar ratio of compound A and fumaric acid is 1:1; Preferably, the fumarate salt of the compound A is crystal form XII; The XRPD pattern of the crystalline form XII includes characteristic peaks at diffraction angles (2θ) of about 7.2±0.2°, 10.9±0.2°, 20.9±0.2° and 27.5±0.2°; It preferably includes diffraction angles (2θ) at about 7.2±0.2°, 10.3±0.2°, 10.9±0.2°, 15.0±0.2°, 20.9±0.2°, 21.6±0.2°, 24.2±0.2° and 27.5±0.2° characteristic peaks at; Optimum includes at about 7.2±0.2°, 7.8±0.2°, 10.3±0.2°, 10.9±0.2°, 13.0±0.2°, 14.5±0.2°, 15.0±0.2°, 17.6±0.2°, 20.9±0.2°, Characteristic peaks at diffraction angles (2θ) of 21.6±0.2°, 22.9±0.2°, 24.2±0.2°, 25.9±0.2°, 27.5±0.2° and 31.0±0.2°.

In a more preferred embodiment, the XRPD pattern of the Form XII includes peaks at the following diffraction angles (2θ): Peak number 2θ ( ^o ) ± 0.2 ^o I% Peak number 2θ ( ^o ) ± 0.2 ^o I% Peak number 2θ I% 1 7.2° 100 7 15.0° 55.4 13 22.9° 44.3 2 7.8° 38.2 8 17.6° 22.8 14 24.2° 71.4 3 10.3° 51.0 9 20.3° 51.6 15 25.9° 36.1 4 10.9° 90.2 10 20.9° 93.6 16 27.5° 86.3 5 13.0° 48.2 11 21.6° 55.8 17 31.0° 20.5 6 14.5° 31.9 12 22.7° 40.6

In a more preferred embodiment, the XRPD pattern of Form XII includes peaks at substantially the same diffraction angle (2Θ) as shown in FIG. 33 . In the most preferred embodiment, the XRPD peak positions of the crystalline form XII are substantially the same as those shown in FIG. 33 .

In a more preferred embodiment, the DSC pattern of Form XII includes an endothermic peak at about 102°C.

In a more preferred embodiment, the Form XII has a weight loss of about 1.1% when heated to about 60°C and about 4.1% weight loss at about 60-150°C in thermogravimetric analysis.

In a more preferred embodiment, the DSC-TGA pattern of the crystalline form XII includes substantially the same characteristic peaks as shown in FIG. 34 . In the most preferred embodiment, the DSC-TGA pattern of the crystalline form XII is substantially the same as that shown in FIG. 34 .

In some embodiments, the present invention provides a method of preparing Form XII, comprising adding Compound A to an alcoholic solvent (preferably an alcohol having 1-6 carbon atoms, including but not limited to methanol, ethanol, 1- Propanol (n-propanol), 2-propanol (isopropanol), 1-butanol, 2-butanol and tert-butanol), heated (for example, heated to 40-80°C, preferably 55°C or 60°C ) to dissolve compound A, then add fumaric acid (preferably a methanol or ethanol solution of fumaric acid), drop to room temperature and stir, filter and dry as appropriate to obtain crystals, wherein the molar ratio of compound A and fumaric acid is It is 1:(1-1.3), preferably about 1:1. Pharmaceutical compositions, methods of treatment and uses

In some embodiments, the present invention provides pharmaceutical compositions comprising a salt of Compound A of the present invention, or a crystalline form thereof, and one or more pharmaceutically acceptable carriers.

In some embodiments, the present invention provides the use of a salt of Compound A of the present invention or a crystalline form thereof in the manufacture of a medicament for the prevention or treatment of a disease modulated by a P2X3 and/or P2X2/3 receptor antagonist.

In some embodiments, the present invention provides a salt of Compound A of the present invention, or a crystalline form thereof, for use in the prevention or treatment of diseases modulated by P2X3 and/or P2X2/3 receptor antagonists.

In some embodiments, the present invention provides a method of preventing or treating a disease modulated by a P2X3 and/or P2X2/3 receptor antagonist, comprising administering to an individual (preferably a mammal) in need thereof a prophylactically or therapeutically effective amount of a Any one or more of the salts of Compound A of the present invention or their crystalline forms.

In a preferred embodiment, the diseases modulated by the P2X3 and/or P2X2/3 receptor antagonists are selected from urinary tract diseases, and the urinary tract diseases are selected from bladder volume reduction, urinary frequency, urge incontinence, stress urinary incontinence, Overactive bladder, benign prostatic hypertrophy, prostatitis, detrusor hyperreflexia, nocturia, urgency, pelvic hypersensitivity, urethritis, pelvic pain syndrome, prostate pain, cystitis, and idiopathic bladder hypersensitivity; pain disorders, The pain disease is selected from inflammatory pain, surgical pain, visceral pain, dental pain, premenstrual pain, central pain, burn pain, migraine and cluster headache; nerve injury, neuritis, neuralgia, poisoning, ischemic injury, Interstitial cystitis, cancer pain, viral, parasitic or bacterial infections, post-traumatic injury, and pain associated with irritable bowel syndrome; diseases of the cardiovascular system, preferably hypertension; respiratory diseases, The respiratory disease is selected from chronic obstructive pulmonary disease, asthma and bronchospasm; the gastrointestinal disease is selected from irritable bowel syndrome (preferably diarrhea-predominant irritable bowel syndrome), inflammatory bowel disease, biliary colic pain, renal colic, and pain associated with gastrointestinal distension.

The term "pharmaceutically acceptable carrier" as used herein refers to a diluent, adjuvant, excipient or vehicle with which the therapeutic agent is administered and which is suitable for contact within the scope of sound medical judgment Human and/or other animal tissue without undue toxicity, irritation, allergic reactions, or other problems or complications commensurate with a reasonable benefit/risk ratio.

Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil , sesame oil, etc. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. Physiological saline and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, nonfat dry milk, glycerin, propylene glycol, water, Ethanol etc. The composition may also contain minor amounts of wetting agents, emulsifying agents or pH buffering agents as desired. Oral formulations may contain standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).

The compositions of the present invention may act systemically and/or locally. For this purpose, they can be administered by a suitable route, for example by injection, intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or transdermal administration; or by oral, buccal, nasal, transmucosal, topical, It is administered in the form of an ophthalmic formulation or by inhalation.

For these routes of administration, the compositions of the present invention may be administered in suitable dosage forms.

The dosage form can be a solid preparation, semi-solid preparation, liquid preparation or gaseous preparation, specifically including but not limited to tablets, capsules, powders, granules, lozenges, hard candies, powders, sprays, creams, ointments , suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, suspensions, elixirs, syrups.

The pharmaceutical compositions of the present invention can be prepared by any method well known in the art, such as by mixing, dissolving, granulating, sugar coating, milling, emulsifying, lyophilizing, and the like.

The term "therapeutically effective amount" as used herein refers to the amount of a salt of Compound A that, when administered, will alleviate to some extent one or more symptoms of the condition being treated.

The dosing regimen can be adjusted to provide the best desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is noted that dosage values may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. It is further understood that for any particular individual, the specific dosing regimen should be adjusted over time according to the needs of the individual and the professional judgment of the person administering or supervising the administration of the composition.

The amount of Compound A salt of the present invention administered will depend on the individual being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound, and the judgment of the prescribing physician. In general, effective doses range from about 0.0001 to about 50 mg per kg of body weight per day, eg, from about 0.01 to about 10 mg/kg/day (single or divided administration). For a 70 kg person, this would add up to about 0.007 mg/day to about 3500 mg/day, eg, about 0.7 mg/day to about 700 mg/day. In some cases, dosage levels not higher than the lower end of the foregoing ranges may be sufficient, while in other cases larger doses may be employed without causing any deleterious side effects, provided that the larger dose is first used Divide into several smaller doses to be administered throughout the day.

The content or amount of the salt of Compound A of the present invention in the pharmaceutical composition may be about 0.01 mg to about 1000 mg, suitably 0.1-500 mg, preferably 0.5-300 mg, more preferably 1-150 mg, particularly preferably 1-50 mg, such as 1.5 mg, 2 mg, 4 mg, 10 mg, and 25 mg, etc.

As used herein, the term "treating", unless otherwise specified, means reversing, alleviating, inhibiting the progression of, or preventing the disorder or condition to which such term is applied, or one or more symptoms of such disorder or condition Such a disorder or condition or one or more symptoms of such a disorder or condition.

An "individual" as used herein includes a human or non-human animal. Exemplary human subjects include human subjects (referred to as patients) or normal subjects with a disease (eg, a disease described herein). "Non-human animals" in the present invention include all vertebrates, such as non-mammals (eg birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (eg sheep, dogs, cats, cows, pigs, etc.). Example

The present invention will be explained in more detail below with reference to the embodiments. The embodiments of the present invention are only used to illustrate the technical solutions of the present invention, but not to limit the scope of the present invention. Those with ordinary knowledge in the technical field to which the present invention pertains can perform some non-standard work. The essential improvement and adjustment still belong to the protection scope of the present invention.

Unless otherwise stated, the starting materials and reagents used in the following examples are commercially available or can be prepared by known methods.

The detection instruments and conditions used in the following examples are as follows: (1) X-ray powder diffraction (XRPD) (a) Instrument model: Bruker D8 advance, equipped with LynxEye detector Test conditions: the anode target material is copper, and the light pipe is set to (40KV 40mA), the 2θ scan angle of the sample is from 3° to 40°, and the scan step size is 0.02°. (b) Instrument model: Bruker D2 phaser Test conditions: the anode target material is copper, the light pipe is set to (40KV 40mA), the 2θ scanning angle of the sample is from 4° to 50°, and the scanning step is 0.02°. (2) Differential Scanning Calorimetry (DSC) Instrument model: (a) TA Discovery DSC 250 (TA Instruments, US); (b) TA Discovery DSC 25 (TA Instruments, US) Test conditions: heating rate at 10°C /min, dry nitrogen was used as purge gas. (3) Thermogravimetric analysis (TGA) Instrument model: (a) Discovery TGA 55 (TA Instruments, US); (b) TGA 4000 (PerkinElmer, Germany) Test conditions: automatic weighing in a heating furnace, heating rate at 10°C /min, dry nitrogen was used as purge gas. (4) Polarizing Microscope Analysis (PLM) Instrument Model: Polarizing Microscope ECLIPSE LV100POL (Nikon, JPN) (5) Nuclear Magnetic Resonance ( ¹ H NMR) Instrument Model: Bruker Advance 300, equipped with B-ACS 120 automatic sampling system (6 ) Dynamic moisture adsorption and desorption analysis (DVS) Instrument model: DVS Intrinsic (SMS, UK) Test conditions: using gradient mode, the humidity range is 0% to 90%, the humidity increment of each gradient is 10%, and the maintenance of each gradient is 10%. time is 1h

第一步： Example 1 : Preparation of 5-((2- ethynyl- 5- isopropylpyridin- 4 -yl ) oxy ) pyrimidine -2,4- diamine ( Compound A) ( refer to PCT/CN2018/112829 , the The entirety of which is hereby incorporated by reference )

first step:

Compound A - 1 (100 g, 0.54 mol) was dissolved in 1,4-dioxane (700 mL), starting material SM1 (136 g, 0.81 mol), K ₂ CO ₃ (149 g, 1.08 mol) and Pd(PPh ₃ ) ₄ (6.2 g, 5.4 mmol) were added in this order, and then pure water (35 mL) was added, followed by nitrogen replacement 3 times. Under the protection of nitrogen, the reaction solution was reacted at 100˚C for 18 hours. LC-MS detected that the reaction of the raw materials was basically complete. The reaction solution was cooled to room temperature, filtered, the filter cake was washed with 1,4-dioxane (200 mL), the filtrate was concentrated under reduced pressure to remove 1,4-dioxane, and then pure water (200 mL) was added. mL), extracted with ethyl acetate (400 mL × 3), combined the organic phases, added anhydrous sodium sulfate (100 g), dried for 30 min, filtered, and concentrated under reduced pressure to obtain the crude product (crude product), which was subjected to silica gel column chromatography (chromatography) separation and purification (petroleum ether:ethyl acetate=20:1～10:1) to obtain compound A-2 (79 g, yellow oil, yield: 99.75%). ¹ H NMR (400 MHz, DMSO -d ₆ ) δ 8.37 (d, J = 5.6 Hz, 1H), 8.22 (s, 1H), 7.04 (d, J = 5.6 Hz, 1H), 5.18 (s, 1H) , 5.09 (s, 1H), 3.85 (s, 3H), 2.05 (s, 3H); MS m/z (ESI): 150.0 [M+H] ⁺ . Second step:

Compound A-2 (79 g, 0.53 mol) was dissolved in anhydrous methanol (700 mL), 10% palladium/carbon (16 g) was added, and the reaction solution was reacted under hydrogen (0.4 MPa) at room temperature for 18 hours, LC -MS detection, there is still a small amount of raw material remaining, additional palladium/carbon (4 g), continue to react at room temperature under hydrogen (0.4 MPa) for 18 hours, LC-MS detection, the raw material reaction is complete. The reaction solution was filtered, the filter cake was washed with methanol (100 mL), and the filtrate was concentrated under reduced pressure to obtain crude compound A-3 (80 g, orange oily liquid, yield: 99.96%). ¹ H NMR (400 MHz, DMSO -d ₆ ) δ 8.31 (d, J = 5.6 Hz, 1H), 8.28 (s, 1H), 6.98 (d, J = 5.6 Hz, 1H), 3.86 (s, 3H) , 3.21 - 3.09 (m, 1H), 1.21 (d, J = 7.2 Hz, 6H); MS m/z (ESI): 152.1 [M+H] ⁺ . Step 3:

The compound N,N-dimethylethanolamine (46.3 g, 0.52 mol) was dissolved in n-hexane (400 mL), under nitrogen protection, cooled to -15˚C～-20˚C, and 2.4 M/ L of n-butyllithium (434 mL, 1.04 mol) was added dropwise, kept for 30 minutes, and then slowly added dropwise the toluene solution of compound A-3 (40 g, 0.26 mol) at -15°C～-20°C (200 mL), after the dropwise addition, the temperature was kept for 30 minutes, the reaction solution was cooled to -70°C, and a solution of carbon tetrabromide (172.4 g, 0.52 mol) in toluene (500 mL) was slowly added dropwise, and the temperature was controlled at - 70˚C～-75˚C, the dropwise addition was completed, and the temperature was kept for 1 hour. LC-MS detected the completion of the reaction of the raw materials, quenched by adding water (500 mL), and extracted with ethyl acetate (500 mL × 3), and the organic phases were combined, Washed once with saturated brine (500 mL), then dried with anhydrous sodium sulfate (400 g) for half an hour, filtered, concentrated, and the crude product was subjected to silica gel column chromatography (petroleum ether:ethyl acetate=200:1～50:1) Compound A - 4 was isolated (25 g, pale yellow oily liquid, yield: 41.81%). ¹ H NMR (400 MHz, DMSO -d ₆ ) δ 8.06 (s, 1H), 7.20 (s, 1H), 3.89 (s, 3H), 3.13-3.05 (m, 1H), 1.18 (d, J = 6.8 Hz, 6H); MS m/z (ESI): 229.9 [M+H] ⁺ . Fourth step:

Compound A - 4 (25 g, 0.11 mol) was dissolved in dichloromethane (300 mL), cooled to 0°C to 5°C under nitrogen protection, and boron tribromide solution (140.3 g) was slowly added. , 0.55 mol), after the addition, the reaction solution was heated to reflux, reacted for 18 hours, detected by LC-MS, and the reaction of the raw materials was completed. The reaction solution was lowered to room temperature and slowly dropped into 500 g of ice. After the dropwise addition, saturated sodium bicarbonate solution was added dropwise to adjust to pH=7～8, filtered, and the filter cake was soaked in ethyl acetate (400 mL). Washed three times, the filtrate was separated, the aqueous phase was extracted with ethyl acetate (400 mL x 3) again, all organic phases were combined, anhydrous sodium sulfate (500 g) was added, dried for half an hour, filtered, and the filtrate was concentrated under reduced pressure to obtain compound A - 5 (20 g, pale yellow solid, yield: 84.17%). ¹ H NMR (400 MHz, DMSO -d ₆ ) δ 11.11 (s, 1H), 7.99 (s, 1H), 6.90 (s, 1H), 3.10 - 3.02 (m, 1H), 1.18 (d, J = 6.8 Hz, 6H); MS m/z (ESI): 215.9 [M+H] ⁺ . Step 5:

Compound A - 5 (10 g, 0.047 mol) was dissolved in DMF (50 mL), potassium carbonate (12.8 g, 0.093 mol) and bromoacetonitrile (8.4 g, 0.07 mol) were added in sequence under nitrogen protection, the The mixture was stirred under warm conditions for 2 hours, and the reaction of the raw materials was detected by LC-MS. Add water (50 mL) to quench, extract with ethyl acetate (50 mL×4), wash the combined organic phase with saturated brine (50 mL×3), add anhydrous sodium sulfate to the organic phase, dry for half an hour, filter , the filtrate was concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether:ethyl acetate=20:1～5:1) to obtain compound A - 6 (4 g, pale yellow solid, yield: 33.38%). ¹ H NMR (400 MHz, DMSO -d ₆ ) δ 8.18 (s, 1H), 7.40 (s, 1H), 5.37 (s, 2H), 3.14 - 3.06 (m, 1H), 1.21 (d, J = 6.8 Hz, 6H); MS m/z (ESI): 254.8 [M+H] ⁺ . Step 6:

Compound A - 6 (4 g, 0.016 mol) was dissolved in DMF (50 mL), under nitrogen protection, tert-butoxybis(dimethylamino)methane (8.2 g, 0.048 mol) was added, heated to 100˚C, stirred for 2 hours, and LC-MS detected the completion of the reaction of the raw materials. The reaction solution was cooled to room temperature, quenched by adding water (50 mL), then extracted with ethyl acetate (50 mL × 3), the organic phase was washed with saturated brine (50 mL × 3), and anhydrous sulfuric acid was added to the organic phase Sodium was dried for half an hour, filtered, the filtrate was concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether:ethyl acetate=10:1～5:1) to obtain compound A - 7 (3.8 g, pale yellow solid, yield : 66.90%). MS m/z (ESI): 309.7 [M-45+H] ⁺ . Seventh step:

Compound A - 7 (3.54 g, 0.01 mol) was dissolved in DMF (25 mL), aniline hydrobromide (2.08 g, 0.012 mol) was added under nitrogen protection, heated to 100˚C, stirred for 2 hours , LC-MS detection of raw materials reaction completed. The reaction solution was cooled to room temperature, quenched by adding water (25 mL), extracted with ethyl acetate (20 mL×3), the organic phase was washed with saturated brine (20 mL×3), dried over anhydrous sodium sulfate for half an hour, Filtration, the filtrate was concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether:ethyl acetate=20:1～5:1) to obtain compound A - 8 (3.1 g, pale yellow solid, yield: 86.59%). ¹ H NMR (400 MHz, DMSO -d ₆ ) δ 9.36 (d, J = 12.8 Hz, 1H), 8.28 (s, 1H), 7.95 (d, J = 12.8 Hz, 1H), 7.32 - 7.24 (m, 4H), 7.20 (s, 1H), 6.99 (t, J = 7.2 Hz, 1H), 3.31 - 3.26 (m, 1H), 1.28 (d, J = 6.8 Hz, 6H); MS m/z (ESI) : 357.7 [M+H] ⁺ . Step 8:

Guanidine hydrochloride (2.4 g, 25.2 mmol) was added to absolute ethanol (50 mL), sodium methoxide (2.4 g, 25.2 mmol) was added under nitrogen protection, stirred at room temperature for half an hour, and then compound A- 8 (3 g, 8.4 mmol), after the addition was completed, the reaction solution was heated to reflux and reacted for 18 hours. LC-MS detected that the reaction of the raw materials was completed. The reaction solution was cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (DCM:MeOH=50:1～20:1) to obtain compound A-9 (900 mg, pale yellow solid, yield : 33.17%, compound 2). ¹ H NMR (400 MHz, DMSO -d ₆ ) δ 8.19 (s, 1H), 7.62 (s, 1H), 6.56 (s, 1H), 6.47 (s, 2H), 6.06 (s, 2H), 3.32 - 3.27 (m, 1H), 1.28 (d, J = 6.8 Hz, 6H); MS m/z (ESI): 323.7 [M+H] ⁺ . Step 9 :

Compound A-9 (3 g, 9.29 mmol) was dissolved in 1,4-dioxane (40 mL), trimethylsilylacetylene (9 g, 92.9 mmol), DIEA (12 g, 92.9 mmol) were dissolved ), CuI (0.6 g) and Pd(PPh ₃ ) ₂ Cl ₂ (0.6 g) were added in sequence, and nitrogen was replaced three times. Under the protection of nitrogen, the reaction solution was reacted at 50 ^o C for 2 hours. LC-MS detected that the reaction of the raw materials was basically complete. The reaction solution was cooled to room temperature, filtered, the filter cake was washed with 1,4-dioxane (10 mL), the filtrate was concentrated under reduced pressure to remove the dioxane, then pure water (100 mL) was added, and the mixture was washed with ethyl acetate. Ester (100 mL × 3) was extracted, the organic phases were combined, anhydrous sodium sulfate (20 g) was added to dry for 30 min, filtered, and concentrated under reduced pressure to obtain the crude product, which was separated by silica gel column chromatography (petroleum ether:ethyl acetate=20: 1～5:1) was purified to obtain compound A-10 (2 g, yield 63.1%). MS m/z (ESI): 341.9 [M+H] ⁺ . Tenth step:

Compound A-10 (2 g, 5.87 mmol) was dissolved in THF (20 mL) and TBAF (1.53 g, 5.87 mmol) was added. The reaction was carried out at room temperature for 10 minutes, and the reaction of the starting materials was detected by LC-MS. The reaction solution was spin-dried to obtain an oily residue. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:3) to obtain Compound A (0.7 g, yellow solid, yield 44.6%). ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 8.33 (s, 1H), 7.56 (s, 1H), 6.50 (s, 1H), 6.41 (s, 2H), 6.01 (s, 2H), 4.20 ( s, 1H), 3.37 - 3.31 (m, 1H), 1.28 (d, J = 6.8 Hz, 6H). MS m/z (ESI): 269.8 [M+H] ⁺ .

Example 2 : Preparation of compound A hydrochloride ( molar ratio 1:1) crystal form Ia ( method 1 ) 5.0 g of compound A was added to 100 mL of absolute ethanol, heated to 60°C, and stirred at this temperature until the solid is completely dissolved. 1.6 mL of concentrated hydrochloric acid was slowly added dropwise, and the reaction solution was slowly cooled to room temperature and continued to be stirred for 1 h. The solid was collected by filtration and dried in vacuo at 40°C overnight to give crystals. The XRPD pattern is shown in Figure 1 after X-ray powder diffraction detection; the DSC and TGA patterns are shown in Figure 2 after DSC and TGA analysis; the sample is observed under a scanning electron microscope, and the crystal morphology is shown in Figure 3. Show. ¹ H NMR (300 MHz, DMSO- d ₆ ) δ: 1.29 (d, 6H), 3.33 (m, 1H), 4.29 (s, 1H), 7.17 (s, 1H), 7.71 (br d, 2H), 7.96 (s, 1H), 8.10 (br d, 1H), 8.42 (s, 2H), 12.35 (br d, 1H).

Example 3 : Preparation of Compound A hydrochloride ( molar ratio 1:1) crystal form Ia ( method 2 ) 1.0 g of Compound A was added to 100 mL of acetone, heated to 50°C, and stirred at this temperature for 30 min. 0.93 mL of 4N hydrochloric acid was slowly added dropwise, the reaction solution was slowly cooled to room temperature, and the stirring was continued overnight. The solid was collected by filtration and dried in vacuo at 50°C overnight to give crystals. The XRPD pattern of X-ray powder diffraction is the same as that in FIG. 1 . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ: 1.29 (d, 6H), 3.33 (m, 1H), 4.29 (s, 1H), 7.17 (s, 1H), 7.71 (br d, 2H), 7.96 (s, 1H), 8.10 (br d, 1H), 8.42 (s, 2H), 12.35 (br d, 1H).

Example 4 : Preparation of Compound A hydrochloride ( 1:1 molar ratio ) crystal form Ib 1.0 g of Compound A was added to 200 mL of ethyl acetate, heated to 50°C, and stirred at this temperature for 30 min. 0.93 mL of 4N hydrochloric acid was slowly added dropwise, the reaction solution was slowly cooled to room temperature, and the stirring was continued overnight. The solid was collected by filtration and dried in vacuo at 50°C overnight to give crystals. Detected by X-ray powder diffraction, its XRPD pattern is shown in Figure 4; by DSC and TGA analysis, its DSC pattern and TGA pattern are shown in Figure 5 and Figure 6, respectively. ¹ H NMR (300 MHz, DMSO- d ₆ ) δ: 1.29 (d, 6H), 3.33 (m, 1H), 4.29 (s, 1H), 7.17 (s, 1H), 7.71 (br d, 2H), 7.96 (s, 1H), 8.10 (br d, 1H), 8.42 (s, 2H), 12.35 (br d, 1H).

Example 5 : Preparation of compound A hydrochloride ( molar ratio 1:2) crystal form II 5.0 g of compound A was added to 100 mL of absolute ethanol, heated to 60°C, and stirred at this temperature until the solid was completely dissolved , 3.2 mL of concentrated hydrochloric acid was slowly added dropwise, and the reaction solution was slowly cooled to room temperature and continued to be stirred for 1 h. The solid was collected by filtration and dried in vacuo at 40°C overnight to give crystals. Detected by X-ray powder diffraction, its XRPD pattern is shown in Figure 7; by DSC and TGA analysis, its DSC and TGA patterns are shown in Figure 8. ¹ H NMR (300 MHz, DMSO- d ₆ ) δ: 1.30 (d, 6H), 3.41 (m, 1H), 4.67 (s, 1H), 7.46 (s, 1H), 7.83 (br d, 2H), 8.06 (d, 2H), 8.52 (d, 2H), 12.57 (br d, 1H).

Example 6 : Preparation of compound A citrate ( mol ratio 1:0.5) crystal form III 5.0 g of compound A was added to 280 mL of absolute ethanol, heated to 60°C, and stirred at this temperature until the solid was completely dissolved . 37.2 mL of 0.5M citric acid methanol solution was slowly added dropwise, and the reaction solution was slowly cooled to room temperature and continued to be stirred for 1.5 h. The solid was collected by filtration and dried in vacuo at 50°C overnight to give crystals. The XRPD pattern is shown in Figure 9 by X-ray powder diffraction; the DSC and TGA patterns are shown in Figure 10 by DSC and TGA analysis; the sample is observed under a scanning electron microscope, and the crystal morphology is shown in Figure 11 . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ: 1.30 (d, 6H), 2.64 (dd, 2H), 3.35 (m, 1H), 4.24 (s, 1H), 6.33 (s, 2H), 6.64 ( s, 1H), 6.76 (br d, 2H), 7.65 (s, 1H), 8.38 (s, 1H), 10.93 (br d, 2H).

Example 7 : Preparation of Compound A sulfate ( molar ratio 1:0.5) Form IV 5.0 g of Compound A was added to 280 mL of absolute ethanol, heated to 55°C, and stirred at this temperature until the solid was completely dissolved. 5.2 mL of 1.8M sulfuric acid ethanol solution was slowly added dropwise, and the reaction solution was slowly lowered to room temperature and continued to be stirred for 6.5 h. The solid was collected by filtration and dried in vacuo at 50°C overnight to give crystals. Through X-ray powder diffraction detection, its XRPD pattern is shown in Figure 12; after DSC and TGA analysis, its DSC and TGA patterns are shown in Figure 13. ¹ H NMR (300 MHz, DMSO- d ₆ ) δ: 1.31 (d, 6H), 3.38 (m, 1H), 4.30 (s, 1H), 7.06 (s, 1H), 7.31 (s, 2H), 7.88 ( s, 3H), 8.44 (s, 1H), 10.79 (br d, 1H).

Example 8 : Preparation of compound A sulfate ( molar ratio 1:1) crystal form V 5.0 g of compound A was added to 280 mL of absolute ethanol, heated to 55°C, and stirred at this temperature until the solid was completely dissolved, 10.5 mL of 1.8M sulfuric acid ethanol solution was slowly added dropwise, the reaction solution was slowly lowered to room temperature, and the stirring was continued for 6.5 h. The solid was collected by filtration and dried in vacuo at 50°C overnight to give crystals. Through X-ray powder diffraction detection, its XRPD pattern is shown in Figure 14; after DSC and TGA analysis, its DSC and TGA patterns are shown in Figure 15. ¹ H NMR (300 MHz, DMSO- d ₆ ) δ: 1.31 (d, 6H), 3.34 (m, 1H), 4.32 (s, 1H), 7.20 (s, 1H), 7.64 (s, 2H), 7.95 ( s, 1H), 8.10 (s, 1H), 8.44 (s, 1H), 8.49 (s, 1H), 11.99 (br d, 1H).

Example 9 : Preparation of compound A p-toluenesulfonate (molar ratio 1:1) crystal form VI 5.0 g of compound A was added to 290 mL of acetone, heated to 50 ° C, and stirred at this temperature for 1 h, slowly 37.2 mL of 0.5M p-toluenesulfonic acid methanol solution was added dropwise, the reaction solution was concentrated to dryness under reduced pressure, 95 mL of acetone was added, and stirring was continued at room temperature for 48 h. The solid was collected by filtration to obtain crystals. Through X-ray powder diffraction detection, its XRPD pattern is shown in Figure 16; after DSC and TGA analysis, its DSC and TGA patterns are shown in Figure 17. ¹ H NMR (300 MHz, DMSO- d ₆ ) δ: 1.30 (d, 6H), 2.29 (s, 3H), 3.33 (m, 1H), 4.31 (s, 1H), 7.12 (d, 2H), 7.18 ( s, 1H), 7.47 (d, 2H), 7.63 (br d, 2H), 7.94 (s, 1H), 8.09 (br d, 1H), 8.43 (s, 1H), 8.49 (br d, 1H), 11.97 (br d, 1H).

Example 10 : Preparation of compound A mesylate (molar ratio 1:1) crystal form VII 5.0 g of compound A was added to 190 mL of tetrahydrofuran, heated to 50 ° C, and stirred at this temperature for 1 h, slowly dripping 1.2 mL of methanesulfonic acid was added, and the reaction solution was slowly cooled to room temperature and continued to stir overnight. The solid was collected by filtration to obtain crystals. The XRPD pattern is shown in Figure 18 by X-ray powder diffraction; the DSC and TGA patterns are shown in Figure 19 by DSC and TGA analysis; the sample is observed under a scanning electron microscope, and the crystal morphology is shown in Figure 20 . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ: 1.32 (d, 6H), 2.38 (s, 3H), 3.35 (m, 1H), 4.39 (s, 1H), 7.26 (s, 1H), 7.70 ( br d, 2H), 7.98 (s, 1H), 8.10 (s, 1H), 8.49 (d, 2H), 12.10 (br d, 1H).

Example 11 : Preparation of compound A mesylate (molar ratio 1:2) crystal form VIII 5.0 g of compound A was added to 190 mL of tetrahydrofuran, heated to 50°C, and stirred at this temperature for 1 h, slowly dripping 2.4 mL of methanesulfonic acid was added, and the reaction solution was slowly cooled to room temperature and continued to stir overnight. The solid was collected by filtration to obtain crystals. The XRPD pattern is shown in Figure 21 through X-ray powder diffraction detection; the DSC and TGA patterns are shown in Figure 22 after DSC and TGA analysis; the sample is observed under a scanning electron microscope, and the crystal morphology is shown in Figure 23 . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ: 1.32 (d, 6H), 2.38 (s, 6H), 3.38 (m, 1H), 4.54 (s, 1H), 7.37 (s, 1H), 7.70 ( br d, 2H), 8.00 (s, 1H), 8.11 (s, 1H), 8.51 (d, 2H), 12.08 (br d, 1H).

Example 12 : Preparation of Compound A Phosphate ( 1:1 Molar Ratio ) Crystal Form IX 5.0 g of Compound A was added to 150 mL of absolute ethanol, heated to 55°C, stirred at this temperature for 1 h, slowly added dropwise 1.3 mL of 85% phosphoric acid (14.5 mol/L), the reaction solution was slowly cooled to room temperature and then continued to stir for 2 h. The solid was collected by filtration and dried in vacuo at 40°C overnight to give crystals. The XRPD pattern is shown in Figure 24 by X-ray powder diffraction; the DSC and TGA patterns are shown in Figure 25 by DSC and TGA analysis; the sample is observed under a scanning electron microscope, and the crystal morphology is shown in Figure 26 . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ: 1.30 (d, 6H), 3.35 (m, 1H), 4.23 (s, 1H), 6.25 (s, 2H), 6.60 (s, 1H), 6.63 ( s, 2H), 7.62 (s, 1H), 8.38 (s, 1H).

Example 13 : Preparation of compound A maleate (mol ratio 1:1) crystal form X 5.0 g of compound A was added to 185 mL of absolute ethanol, heated to 60°C, and stirred at this temperature for 1 h, slowly 18.6 mL of 1M maleic acid ethanol solution was added dropwise, and the reaction solution was slowly lowered to room temperature and continued to be stirred for 2 h. The solid was collected by filtration and dried in vacuo at 40°C overnight to give crystals. The XRPD pattern is shown in Figure 27 by X-ray powder diffraction; the DSC and TGA patterns are shown in Figure 28 by DSC and TGA analysis; the sample is observed under a scanning electron microscope, and the crystal morphology is shown in Figure 29 . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ: 1.30 (d, 6H), 3.33 (m, 1H), 4.28 (s, 1H), 6.07 (s, 2H), 7.06 (s, 1H), 7.34 ( br d, 2H), 7.87 (s, 1H), 7.95 (br d, 2H), 8.42 (s, 1H).

Example 14 : Preparation of compound A L- tartrate ( molar ratio 1:1) crystal form XI 5.0 g of compound A was added to 190 mL of absolute ethanol, heated to 60°C, and stirred at this temperature for 1 h, slowly 37.2 mL of 0.5M L-tartaric acid methanol solution was added dropwise, the reaction solution was slowly lowered to room temperature, and the stirring was continued for 2 h. The solid was collected by filtration and dried in vacuo at 40°C overnight to give crystals. The XRPD pattern is shown in Figure 30 by X-ray powder diffraction; the DSC and TGA patterns are shown in Figure 31 by DSC and TGA analysis; the sample is observed under a scanning electron microscope, and the crystal morphology is shown in Figure 32 . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ: 1.32 (d, 6H), 3.36 (m, 1H), 4.25 (s, 1H), 4.28 (d, 2H), 6.21 (s, 2H), 6.61 ( s, 3H), 7.64 (s, 1H), 8.40 (s, 1H).

Example 15 : Preparation of compound A fumarate salt ( molar ratio 1:1) crystal form XII 5.0 g of compound A was added to 190 mL of absolute ethanol, heated to 60°C, and stirred at this temperature for 1 h, slowly 74.4 mL of 0.25M fumaric acid methanol solution was added dropwise, and the reaction solution was slowly lowered to room temperature and continued to be stirred for 2 h. The solid was collected by filtration and dried in vacuo at 40°C overnight to give crystals. Through X-ray powder diffraction detection, its XRPD pattern is shown in Figure 33; after DSC and TGA analysis, its DSC and TGA patterns are shown in Figure 34. ¹ H NMR (300 MHz, DMSO- d ₆ ) δ: 1.32 (d, 6H), 3.38 (m, 1H), 4.24 (s, 1H), 6.15 (d, 2H), 6.53 (s, 2H), 6.58 ( s, 1H), 6.64 (s, 2H), 7.63 (s, 1H), 8.39 (s, 1H). Experiment Example Experiment Example 1 : Moisture Experiment

The hygroscopicity of Compound A hydrochloride form Ia, citrate form III and maleate form X samples was studied by dynamic moisture adsorption analysis (DVS), and the samples before and after DVS determination were subjected to XRPD Detection and spectral comparison. The moisture absorption of the hydrochloride crystal form Ia sample at 90% RH was 1.21%, and the XRPD pattern of the sample did not change before and after DVS measurement. The moisture absorption of the citrate crystal form III sample at 80% RH was 1.69%, and the XRPD pattern of the sample did not change before and after DVS measurement. The moisture absorption of the maleate crystal form X sample at 90% RH was 3.69%, and the XRPD pattern of the sample did not change before and after DVS measurement. Experimental Example 2 : High Temperature Stability Experiment

Compound A hydrochloride crystal form Ia and citrate crystal form III samples were subjected to stability investigation under two conditions of 40°C/75% RH and 60°C for 2 weeks. The XRPD pattern was measured by Bruker D8 advance X-ray powder diffractometer after 1 week and 2 weeks of the experiment (see Figure 35 and Figure 36). The results show that the two salt crystal forms have no change in the crystal form during the stability investigation, and the stability is stable. Excellent sex. Experimental Example 3 : Solubility Test

Compound A hydrochloride form Ia and citrate form III samples were subjected to solubility experiments in FaSSIF (fasting bowel simulated fluid) at 37°C with Compound A free base. Solubility data are shown in the table below. The solubility of the two salt crystal forms in FaSSIF is significantly higher than that of the free base, among which the hydrochloride salt crystal form Ia is about 30 times higher, and the citrate crystal form III is about 4 times higher. sample Solubility (mg/mL) 30 min 2h 24h free base 0.08 0.08 0.11 Hydrochloride salt form Ia 2.18 2.54 3.38 Citrate Form III 0.37 0.33 0.42

In addition to those described herein, various modifications of the invention will be apparent to those of ordinary skill in the art to which the invention pertains from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in this application, including all patents, patent applications, journal articles, books, and any other publications, is incorporated by reference in its entirety.

Figure 1 is the X-ray powder diffraction pattern of Compound A hydrochloride (molar ratio 1:1) Form Ia. Figure 2 is a differential scanning calorimetry (DSC) pattern and a thermogravimetric analysis (TGA) pattern of Compound A hydrochloride (mol ratio 1:1) crystal form Ia. Figure 3 is a scanning electron microscope photograph of Compound A hydrochloride (molar ratio 1:1) Form Ia. Figure 4 is the X-ray powder diffraction pattern of Compound A hydrochloride (mol ratio 1:1) Form Ib. Figure 5 is a differential scanning calorimetry (DSC) pattern of Compound A hydrochloride (molar ratio 1:1) Form Ib. Figure 6 is a thermogravimetric analysis (TGA) pattern of Compound A hydrochloride (molar ratio 1:1) Form Ib. Figure 7 is the X-ray powder diffraction pattern of Compound A hydrochloride (mol ratio 1:2) Form II. Figure 8 is a differential scanning calorimetry (DSC) pattern and a thermogravimetric analysis (TGA) pattern of Compound A hydrochloride (molar ratio 1:2) crystal form II. Figure 9 is an X-ray powder diffraction pattern of Compound A citrate (mol ratio 1:0.5) Form III. Figure 10 is a differential scanning calorimetry (DSC) pattern and a thermogravimetric analysis (TGA) pattern of Compound A citrate (molar ratio 1:0.5) Form III. Figure 11 is a scanning electron microscope photograph of Compound A citrate (mol ratio 1:0.5) Form III. Figure 12 is an X-ray powder diffraction pattern of Compound A sulfate (molar ratio 1:0.5) Form IV. Figure 13 is a differential scanning calorimetry (DSC) pattern and a thermogravimetric analysis (TGA) pattern of Compound A sulfate (molar ratio 1:0.5) Form IV. Figure 14 is the X-ray powder diffraction pattern of Compound A sulfate (molar ratio 1:1) Form V. Figure 15 is a differential scanning calorimetry (DSC) pattern and a thermogravimetric analysis (TGA) pattern of Compound A sulfate (molar ratio 1:1) Form V. Figure 16 is an X-ray powder diffraction pattern of Compound A p-toluenesulfonate (mol ratio 1:1) crystal form VI. Figure 17 is a differential scanning calorimetry (DSC) pattern and a thermogravimetric analysis (TGA) pattern of compound A p-toluenesulfonate (molar ratio 1:1) crystal form VI. Figure 18 is an X-ray powder diffraction pattern of Compound A mesylate (molar ratio 1:1) Form VII. Figure 19 is a differential scanning calorimetry (DSC) pattern and a thermogravimetric analysis (TGA) pattern of Compound A mesylate (molar ratio 1:1) Form VII. Figure 20 is a scanning electron microscope photograph of Compound A mesylate (molar ratio 1:1) Form VII. Figure 21 is the X-ray powder diffraction pattern of Compound A mesylate (mol ratio 1:2) Form VIII. Figure 22 is a differential scanning calorimetry (DSC) pattern and a thermogravimetric analysis (TGA) pattern of Compound A mesylate (molar ratio 1:2) Form VIII. Figure 23 is a scanning electron microscope photograph of Compound A mesylate (molar ratio 1:2) Form VIII. Figure 24 is an X-ray powder diffraction pattern of Compound A phosphate (molar ratio 1:1) Form IX. Figure 25 is a differential scanning calorimetry (DSC) pattern and a thermogravimetric analysis (TGA) pattern of Compound A phosphate (molar ratio 1:1) Form IX. Figure 26 is a scanning electron microscope photograph of Compound A phosphate (1:1 molar ratio) Form IX. Figure 27 is the X-ray powder diffraction pattern of Compound A maleate salt (mol ratio 1:1) Form X. Figure 28 is a differential scanning calorimetry (DSC) pattern and a thermogravimetric analysis (TGA) pattern of Compound A maleate salt (molar ratio 1:1) Form X. Figure 29 is a scanning electron microscope photograph of Compound A maleate salt (molar ratio 1:1) Form X. Figure 30 is an X-ray powder diffraction pattern of Compound A L-tartrate (molar ratio 1:1) Form XI. Figure 31 is a differential scanning calorimetry (DSC) pattern and a thermogravimetric analysis (TGA) pattern of Compound A L-tartrate (molar ratio 1:1) Form XI. Figure 32 is a scanning electron microscope photograph of Compound A L-tartrate (molar ratio 1:1) Form XI. Figure 33 is an X-ray powder diffraction pattern of Compound A fumarate salt (mol ratio 1:1) Form XII. Figure 34 is a differential scanning calorimetry (DSC) pattern and a thermogravimetric analysis (TGA) pattern of Compound A fumarate salt (molar ratio 1:1) Form XII. Figure 35 is a comparison of the X-ray powder diffraction patterns of Compound A hydrochloride (mol ratio 1:1) crystal form Ia before and after the high temperature stability test. Figure 36 is a comparison of the X-ray powder diffraction patterns of Compound A citrate (mol ratio 1:0.5) crystal form III before and after the high temperature stability test.

Claims (54)

a salt of Compound A,

It is an inorganic acid salt or an organic acid salt, wherein the inorganic acid is selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid and any combination thereof; the organic acid is selected from formic acid, acetic acid, acetonitrile acetic acid , trifluoroacetic acid, propionic acid, pyruvic acid, butyric acid, caproic acid, heptanoic acid, undecanoic acid, lauric acid, stearic acid, palmitic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, hexamethylene acid, maleic acid, fumaric acid, lactic acid, L-malic acid, citric acid, L-tartaric acid, benzoic acid, salicylic acid, cinnamic acid, naphthoic acid, pamoic acid, nicotinic acid, orotic acid, Methyl sulfuric acid, dodecyl sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid, ethanedisulfonic acid, isethionic acid, p-toluenesulfonic acid, benzenesulfonic acid, 1,5-naphthalenedisulfonic acid, 2 - Naphthalenesulfonic acid, camphorsulfonic acid, sulfamic acid, glutamic acid, aspartic acid, gluconic acid, glucuronic acid, and any combination thereof. The salt of compound A according to claim 1, wherein the salt is selected from L-tartrate, phosphate, mesylate, maleate, hydrochloride, fumarate, citrate, p-toluenesulfonic acid salts and sulfates. The salt of compound A according to claim 1, which is the hydrochloride salt of compound A. The salt of compound A of claim 3, wherein: the molar ratio of compound A to hydrochloric acid is 1:1; the hydrochloride of compound A is crystal form Ia; and the XRPD pattern of the crystal form Ia is included in about 7.8± Characteristic peaks at diffraction angles (2θ) of 0.2°, 10.4±0.2°, 15.7±0.2°, 20.0±0.2°, 20.7±0.2°, 22.3±0.2° and 26.0±0.2°. The salt of compound A of claim 4, wherein: the XRPD pattern of the crystalline form Ia is included at about 7.8±0.2°, 10.4±0.2°, 11.1±0.2°, 15.7±0.2°, 16.2±0.2°, 20.0±0.2 Characteristic peaks at diffraction angles (2θ) of °, 20.7±0.2°, 22.3±0.2°, 23.7±0.2°, 24.7±0.2°, 26.0±0.2° and 28.8±0.2°. The salt of compound A according to claim 5, wherein: the XRPD pattern of the crystalline form Ia is included at about 7.8±0.2°, 10.4±0.2°, 11.1±0.2°, 14.5±0.2°, 14.7±0.2°, 15.7±0.2 °, 16.2±0.2°, 18.0±0.2°, 20.0±0.2°, 20.7±0.2°, 22.3±0.2°, 23.0±0.2°, 23.7±0.2°, 24.7±0.2°, 25.3±0.2°, 26.0±0.2 Characteristic peaks at diffraction angles (2θ) of °, 26.4±0.2°, 27.0±0.2°, 28.8±0.2°, 29.7±0.2°, 33.9±0.2° and 38.3±0.2°. The salt of compound A of claim 3, wherein: the molar ratio of compound A to hydrochloric acid is 1:1; the hydrochloride of compound A is crystal form Ib; and the XRPD pattern of the crystal form Ib is included in about 5.4± 0.2°, 11.2±0.2° and 20.0±0.2° Characteristic peak at diffraction angle (2θ). The salt of compound A of claim 7, wherein: the XRPD pattern of the crystalline form Ib is included at about 5.4±0.2°, 9.5±0.2°, 11.2±0.2°, 13.6±0.2°, 20.0±0.2°, 20.8±0.2 Characteristic peaks at diffraction angles (2θ) of °, 24.9±0.2° and 25.5±0.2°. The salt of compound A of claim 8, wherein: the XRPD pattern of the crystalline form Ib is included at about 5.4±0.2°, 9.5±0.2°, 11.2±0.2°, 13.6±0.2°, 15.7±0.2°, 17.6±0.2 °, 20.0±0.2°, 20.8±0.2°, 22.1±0.2°, 23.2±0.2°, 23.6±0.2°, 24.1±0.2°, 24.6±0.2°, 24.9±0.2°, 25.5±0.2° and 30.5±0.2 Characteristic peak at the diffraction angle (2θ) of °. The salt of compound A of claim 3, wherein: the molar ratio of compound A and hydrochloric acid is 1:2; the hydrochloride of compound A is crystal form II; and the XRPD pattern of the crystal form II is included in about 13.3± Characteristic peaks at diffraction angles (2θ) of 0.2°, 14.2±0.2°, 21.9±0.2° and 27.4±0.2°. The salt of compound A of claim 10, wherein: the XRPD pattern of the crystal form II is included at about 8.2±0.2°, 11.9±0.2°, 13.3±0.2°, 14.2±0.2°, 16.0±0.2°, 18.3±0.2 °, 19.4±0.2°, 20.0±0.2°, 21.2±0.2°, 21.9±0.2°, 22.9±0.2°, 24.6±0.2°, 26.6±0.2°, 27.4±0.2° and 28.0±0.2° Characteristic peak at diffraction angle (2θ). The salt of compound A of claim 11, wherein: the XRPD pattern of the crystal form II is included at about 8.2±0.2°, 11.9±0.2°, 13.3±0.2°, 14.2±0.2°, 14.8±0.2°, 16.0±0.2 °, 17.8±0.2°, 18.3±0.2°, 19.4±0.2°, 20.0±0.2°, 21.2±0.2°, 21.9±0.2°, 22.6±0.2°, 22.9±0.2°, 23.5±0.2°, 24.6±0.2 Characteristic peaks at diffraction angles (2θ) of °, 25.6±0.2°, 26.6±0.2°, 27.4±0.2°, 28.0±0.2°, 29.7±0.2°, 31.8±0.2° and 34.0±0.2°. The salt of compound A according to claim 1, which is the citrate of compound A. The salt of compound A of claim 13, wherein: the molar ratio of compound A to citric acid is 1:0.5; the citrate salt of compound A is crystal form III; and the XRPD pattern of the crystal form III is included in about 6.9 Characteristic peaks at diffraction angles (2θ) of ±0.2°, 10.8±0.2°, 14.6±0.2°, 20.3±0.2° and 22.5±0.2°. The salt of compound A of claim 14, wherein: the XRPD pattern of the crystal form III is included at about 6.9±0.2°, 10.8±0.2°, 14.6±0.2°, 16.3±0.2°, 20.3±0.2°, 22.5±0.2 Characteristic peaks at diffraction angles (2θ) of °, 23.4±0.2° and 26.6±0.2°. A salt of compound A as claimed in claim 15, wherein: The XRPD pattern of Form III includes at about 6.9±0.2°, 10.8±0.2°, 12.7±0.2°, 14.6±0.2°, 16.3±0.2°, 17.6±0.2°, 18.1±0.2°, 20.3±0.2°, Characteristic peaks at diffraction angles (2θ) of 21.4±0.2°, 22.5±0.2°, 23.4±0.2°, 24.2±0.2°, 25.5±0.2°, 26.0±0.2°, 26.6±0.2° and 27.1±0.2°. The salt of compound A according to claim 1, which is the sulfate of compound A. The salt of compound A of claim 17, wherein: the molar ratio of compound A to sulfuric acid is 1:0.5; the sulfate of compound A is crystal form IV; and the XRPD pattern of the crystal form IV is included in about 8.0±0.2 Characteristic peaks at diffraction angles (2θ) of °, 11.2±0.2°, 20.9±0.2°, 21.8±0.2° and 26.3±0.2°. The salt of compound A of claim 18, wherein: the XRPD pattern of the crystal form IV is included at about 8.0±0.2°, 10.5±0.2°, 11.2±0.2°, 20.9±0.2°, 21.8±0.2°, 22.5±0.2 Characteristic peaks at diffraction angles (2θ) of °, 23.8±0.2° and 26.3±0.2°. The salt of compound A of claim 19, wherein: the XRPD pattern of the crystal form IV is included at about 8.0±0.2°, 10.5±0.2°, 11.2±0.2°, 13.2±0.2°, 15.3±0.2°, 15.9±0.2 °, 16.8±0.2°, 19.0±0.2°, 20.9±0.2°, 21.8±0.2°, 22.5±0.2°, 23.8±0.2°, 24.9±0.2°, 26.3±0.2°, 28.3±0.2°, 29.1±0.2 Characteristic peaks at diffraction angles (2θ) of °, 30.1±0.2° and 37.9±0.2°. The salt of compound A of claim 17, wherein: the molar ratio of compound A to sulfuric acid is 1:1; the sulfate of compound A is crystal form V; and the XRPD pattern of the crystal form V is included in about 7.9±0.2 Characteristic peaks at diffraction angles (2θ) of °, 11.2±0.2°, 20.3±0.2°, 21.7±0.2° and 26.3±0.2°. The salt of compound A of claim 21, wherein: the XRPD pattern of the crystalline form V is included at about 7.9±0.2°, 11.2±0.2°, 20.3±0.2°, 21.7±0.2°, 22.5±0.2°, 23.7±0.2 Characteristic peaks at diffraction angles (2θ) of °, 24.8±0.2° and 26.3±0.2°. The salt of compound A of claim 22, wherein: the XRPD pattern of the crystalline form V is included at about 7.9±0.2°, 10.4±0.2°, 11.2±0.2°, 13.1±0.2°, 15.1±0.2°, 15.7±0.2 °, 15.9±0.2°, 16.6±0.2°, 18.9±0.2°, 20.3±0.2°, 21.0±0.2°, 21.7±0.2°, 22.5±0.2°, 23.7±0.2°, 24.3±0.2°, 24.8±0.2 Characteristic peaks at diffraction angles (2θ) of °, 26.3±0.2°, 28.2±0.2°, 29.1±0.2°, 30.1±0.2° and 37.9±0.2°. The salt of compound A according to claim 1, which is the p-toluenesulfonate of compound A. The salt of compound A according to claim 24, wherein: the molar ratio of compound A and p-toluenesulfonic acid is 1:1; The p-toluenesulfonate salt of Compound A is crystal form VI; and the XRPD pattern of the crystal form VI includes diffraction angles (2θ) at about 9.2±0.2°, 10.8±0.2°, 18.0±0.2° and 19.5±0.2° characteristic peaks at . The salt of compound A of claim 25, wherein: the XRPD pattern of the crystal form VI is included at about 9.2±0.2°, 10.8±0.2°, 17.7±0.2°, 18.0±0.2°, 18.5±0.2°, 19.5±0.2 Characteristic peaks at diffraction angles (2θ) of °, 20.4±0.2°, 21.7±0.2°, 21.9±0.2°, 23.6±0.2° and 28.6±0.2°. The salt of compound A of claim 26, wherein: the XRPD pattern of the crystal form VI is included at about 9.2±0.2°, 10.8±0.2°, 14.9±0.2°, 15.4±0.2°, 17.7±0.2°, 18.0±0.2 °, 18.5±0.2°, 19.5±0.2°, 20.4±0.2°, 21.2±0.2°, 21.7±0.2°, 21.9±0.2°, 23.6±0.2°, 24.5±0.2°, 26.2±0.2°, 28.6±0.2 Characteristic peaks at diffraction angles (2θ) of °, 32.1±0.2° and 32.7±0.2°. The salt of compound A according to claim 1, which is the mesylate of compound A. The salt of compound A according to claim 28, wherein: the molar ratio of compound A and methanesulfonic acid is 1:1; the methanesulfonic acid salt of compound A is crystal form VII; and the XRPD pattern of the crystal form VII is included in Characteristic peaks at diffraction angles (2Θ) of approximately 7.7 ± 0.2°, 10.5 ± 0.2°, 19.0 ± 0.2°, 20.1 ± 0.2° and 20.5 ± 0.2°. The salt of compound A of claim 29, wherein: the XRPD pattern of the crystal form VII is included at about 7.7±0.2°, 10.5±0.2°, 16.2±0.2°, 16.8±0.2°, 19.0±0.2°, 19.9±0.2 Characteristic peaks at diffraction angles (2θ) of °, 20.1±0.2°, 20.5±0.2°, 21.0±0.2°, 22.6±0.2°, 24.0±0.2°, 25.5±0.2° and 26.5±0.2°. The salt of compound A according to claim 30, wherein: the XRPD pattern of the crystal form VII is included at about 6.0±0.2°, 7.7±0.2°, 10.5±0.2°, 11.0±0.2°, 12.3±0.2°, 13.5±0.2 °, 14.0±0.2°, 14.3±0.2°, 14.9±0.2°, 15.5±0.2°, 16.2±0.2°, 16.8±0.2°, 19.0±0.2°, 19.9±0.2°, 20.1±0.2°, 20.5±0.2 °, 21.0±0.2°, 21.4±0.2°, 22.6±0.2°, 23.2±0.2°, 24.0±0.2°, 24.9±0.2°, 25.5±0.2°, 25.8±0.2°, 26.5±0.2°, 27.6±0.2 ° and characteristic peaks at diffraction angles (2θ) of 29.6±0.2°. The salt of compound A according to claim 28, wherein: the molar ratio of compound A and methanesulfonic acid is 1:2; the methanesulfonic acid salt of compound A is crystal form VIII; and the XRPD pattern of the crystal form VIII is included in Characteristic peaks at diffraction angles (2θ) of about 11.0±0.2°, 12.2±0.2°, 13.4±0.2°, 19.9±0.2°, 20.2±0.2°, 21.4±0.2° and 25.8±0.2°. The salt of compound A of claim 32, wherein: the XRPD pattern of the crystal form VIII is included at about 3.2±0.2°, 6.0±0.2°, 11.0±0.2°, 12.2±0.2°, 13.4±0.2°, 19.9±0.2 °, 20.2±0.2°, 21.0±0.2°, 21.4±0.2°, Characteristic peaks at diffraction angles (2θ) of 23.0±0.2°, 23.4±0.2°, 24.9±0.2° and 25.8±0.2°. The salt of compound A of claim 33, wherein: the XRPD pattern of the crystal form VIII is included at about 3.2±0.2°, 6.0±0.2°, 9.4±0.2°, 11.0±0.2°, 12.2±0.2°, 13.4±0.2 °, 14.9±0.2°, 15.5±0.2°, 15.7±0.2°, 17.7±0.2°, 18.1±0.2°, 18.9±0.2°, 19.9±0.2°, 20.2±0.2°, 21.0±0.2°, 21.4±0.2 degrees Characteristic peaks at diffraction angles (2θ) of °, 28.9±0.2°, 30.8±0.2° and 31.5±0.2°. The salt of compound A according to claim 1, which is the phosphate of compound A. The salt of compound A of claim 35, wherein: the molar ratio of compound A to phosphoric acid is 1:1; the phosphate of compound A is crystalline form IX; and the XRPD pattern of the crystalline form IX is included at about 7.0±0.2 Characteristic peaks at diffraction angles (2θ) of °, 10.7±0.2°, 14.6±0.2° and 26.7±0.2°. The salt of compound A of claim 36, wherein: the XRPD pattern of the crystalline form IX is included at about 7.0±0.2°, 10.7±0.2°, 14.6±0.2°, 15.3±0.2°, 18.4±0.2°, 22.3±0.2 Characteristic peaks at diffraction angles (2θ) of °, 23.4±0.2° and 26.7±0.2°. The salt of compound A of claim 37, wherein: the XRPD pattern of the crystal form IX is included at about 7.0±0.2°, 10.7±0.2°, 14.0±0.2°, 14.6±0.2°, 15.3±0.2°, 16.2±0.2 Diffraction angles ( characteristic peak at 2θ). The salt of compound A according to claim 1, which is the maleate salt of compound A. The salt of compound A according to claim 39, wherein: the molar ratio of compound A to maleic acid is 1:1; the maleate salt of compound A is crystal form X; and the XRPD pattern of the crystal form X is included in Characteristic peaks at diffraction angles (2θ) of about 5.4±0.2°, 5.8±0.2°, 13.7±0.2° and 17.1±0.2°. The salt of compound A of claim 40, wherein: the XRPD pattern of the crystal form X is included at about 5.4±0.2°, 5.8±0.2°, 8.9±0.2°, 10.0±0.2°, 13.7±0.2°, 16.0±0.2 Characteristic peaks at diffraction angles (2θ) of °, 17.1±0.2°, 21.7±0.2° and 21.9±0.2°. The salt of compound A of claim 41, wherein: the XRPD pattern of the crystal form X is included at about 5.4±0.2°, 5.8±0.2°, 8.9±0.2°, 10.0±0.2°, 13.7±0.2°, 16.0±0.2 Characteristic peaks at diffraction angles (2θ) of °, 17.1±0.2°, 21.7±0.2°, 21.9±0.2°, 24.1±0.2°, 25.8±0.2° and 27.6±0.2°. The salt of compound A according to claim 1, which is the L-tartrate salt of compound A. The salt of compound A according to claim 43, wherein: the molar ratio of compound A and L-tartaric acid is 1:1; the L-tartrate salt of compound A is crystal form XI; and the XRPD pattern of the crystal form XI is included in Characteristic peaks at diffraction angles (2Θ) of approximately 6.5 ± 0.2°, 14.3 ± 0.2°, 20.8 ± 0.2°, 21.5 ± 0.2° and 25.2 ± 0.2°. The salt of compound A of claim 44, wherein: the XRPD pattern of the crystal form XI is included at about 6.5±0.2°, 10.9±0.2°, 12.6±0.2°, 14.3±0.2°, 16.1±0.2°, 17.3±0.2 Characteristic peaks at diffraction angles (2θ) of °, 18.0±0.2°, 20.8±0.2°, 21.5±0.2°, 22.5±0.2° and 25.2±0.2°. The salt of compound A of claim 45, wherein: the XRPD pattern of the crystal form XI is included at about 6.5±0.2°, 10.3±0.2°, 10.9±0.2°, 12.6±0.2°, 14.3±0.2°, 15.2±0.2 °, 16.1±0.2°, 17.3±0.2°, 18.0±0.2°, 19.4±0.2°, 20.8±0.2°, 21.5±0.2°, 22.0±0.2°, 22.5±0.2°, 23.4±0.2°, 23.8±0.2 °, 24.2±0.2°, 24.8±0.2°, 25.2±0.2°, 25.8±0.2°, 26.7±0.2°, 27.8±0.2°, 28.8±0.2°, 30.1±0.2°, 31.4±0.2°, 33.8±0.2 ° and characteristic peaks at diffraction angles (2θ) of 35.2±0.2°. The salt of compound A according to claim 1, which is the fumarate salt of compound A. The salt of compound A according to claim 47, wherein: the molar ratio of compound A to fumaric acid is 1:1; the fumarate salt of compound A is crystal form XII; and the XRPD pattern of the crystal form XII is included in Characteristic peaks at diffraction angles (2θ) of about 7.2±0.2°, 10.9±0.2°, 20.9±0.2° and 27.5±0.2°. The salt of compound A of claim 48, wherein: the XRPD pattern of the crystalline form XII is included at about 7.2±0.2°, 10.3±0.2°, 10.9±0.2°, 15.0±0.2°, 20.9±0.2°, 21.6±0.2 Characteristic peaks at diffraction angles (2θ) of °, 24.2±0.2° and 27.5±0.2°. The salt of compound A of claim 49, wherein: the XRPD pattern of the crystalline form XII is included at about 7.2±0.2°, 7.8±0.2°, 10.3±0.2°, 10.9±0.2°, 13.0±0.2°, 14.5±0.2 Diffraction angles ( characteristic peak at 2θ). A pharmaceutical composition comprising the salt of any one of claims 1 to 50, and one or more pharmaceutically acceptable carriers. Use of a salt according to any one of claims 1 to 50 in the manufacture of a medicament for the prevention or treatment of diseases mediated by P2X3 and/or P2X2/3 receptor antagonists. The purposes of claim 52, wherein the disease is selected from the group consisting of: urinary tract diseases selected from the group consisting of decreased bladder capacity, urinary frequency, urge incontinence, stress urinary incontinence, overactive bladder, benign prostatic hypertrophy, prostatitis, Detrusor hyperreflexia, nocturia, urgency, pelvic hypersensitivity, urethritis, pelvic pain syndrome, prostatic pain, cystitis, and idiopathic bladder hypersensitivity; pain disorders selected from inflammatory pain, surgical pain , visceral pain, toothache, premenstrual pain, central pain, burn pain, migraine and cluster headache; nerve injury; neuritis; neuralgia; poisoning; ischemic injury; interstitial cystitis; cancer pain; virus, Parasitic or bacterial infection; post-traumatic injury; pain associated with irritable bowel syndrome; cardiovascular system disease; respiratory disease selected from chronic obstructive pulmonary disease, asthma and bronchospasm; gastrointestinal disease, the gastrointestinal tract The disease is selected from irritable bowel syndrome, inflammatory bowel disease, biliary colic, and pain associated with gastrointestinal distension; and Renal colic. The use of claim 53, wherein: the cardiovascular system disease is hypertension; and/or the irritable bowel syndrome is diarrhea-type irritable bowel syndrome.

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